Skip to main content
SpringerLink
Log in

Resistance to Anticancer Antibodies: From Mechanisms to Solutions

  • Chapter
  • First Online:
Resistance to Immunotherapeutic Antibodies in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 2))

  • 1045 Accesses

Abstract

Therapeutic monoclonal antibodies exert their antitumor effect through a variety of mechanisms, including apoptotic induction, extracellular mechanisms and the involvement of the innate and possibly the adaptative immune systems. Due to this complexity there are still few data regarding mechanisms of resistance to monoclonal antibody therapy. In this review, we discuss the available data for three of the best described antibodies, rituximab, trastuzumab and cetuximab. A variety of approaches and strategies has been suggested or are currently being tested to circumvent resistance to these antibodies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADCs:

Antibody–drug conjugates

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ADCP:

Antibody-dependent cellular phagocygtosis

CDC:

Complement-dependent cytotoxicity

CLL:

Chronic lymphocytic leukemia

CRP:

Complement regulatory proteins

DLBCL:

Diffuse large B cell lymphoma

EGFR:

Epidermal growth factor receptor

FcR:

Fc receptor

FL:

Follicular lymphoma

HER2:

Human epidermal growth factor

HGF:

Hepatocyte growth factor

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

IFN:

Interferon

IL:

Interleukin

IGF-1:

Insulin-like growth factor 1

MAbs:

Monoclonal antibodies

mTor:

Mammalian target of rapamycin

MUC4:

Mucin-4

NHL:

Non-hodgkin lymphoma

NK:

Natural killer

OS:

Overall survival

PCD:

Programmed cell death

PFS:

Progression-free survival

RTK:

Receptor tyrosine kinase

TKI:

Tyrosine kinase inhibitor

VEGF:

Vascular endothelial growth factor

References

  1. Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematol Am Soc Hematol Educ Prog. 2007;2007:233–42.

    Google Scholar 

  2. Cvetkovic RS, Perry CM. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs. 2006;66:791–820.

    PubMed  CAS  Google Scholar 

  3. Lim SH, Beers SA, French RR, Johnson PW, Glennie MJ, Cragg MS. Anti-CD20 monoclonal antibodies: historical and future perspectives. Haematologica. 2010;95:135–43.

    PubMed  CAS  Google Scholar 

  4. Friedberg JW. Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy. Hematol Am Soc Hematol Educ Prog. 2005;2005:329–34.

    Google Scholar 

  5. Haidar JH, Shamseddine A, Salem Z, Mrad YA, Nasr MR, Zaatari G, Bazarbachi A. Loss of CD20 expression in relapsed lymphomas after rituximab therapy. Eur J Haematol. 2003;70:330–2.

    PubMed  Google Scholar 

  6. Kennedy GA, Tey SK, Cobcrft R, Marlton P, Cull G, Grimmett K, Thomson D, Gill D. Incidence and nature of CD20-negative relapses following rituximab therapy in aggressive B-cell non-Hodgkin’s lymphoma: a retrospective review. Br J Haematol. 2002;119:412–6.

    PubMed  CAS  Google Scholar 

  7. Kahl BS. Eastern Cooperative Oncology Group 4402: Rituximab Extended Schedule or Retreatment Trial (RESORT). Clin Lymphoma Myeloma. 2006;6:423–6.

    PubMed  CAS  Google Scholar 

  8. Terui Y, Mishima Y, Sugimura N, Kojima K, Sakurai T, Mishima Y, Kuniyoshi R, Taniyama A, Yokoyama M, Sakajiri S, Takeuchi K, Watanabe C, Takahashi S, Ito Y, Hatake K. Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin’s lymphoma. Clin Cancer Res. 2009;15:2523–30.

    PubMed  CAS  Google Scholar 

  9. Mishima Y, Terui Y, Takeuchi K, Matsumoto-Mishina Y, Matsusaka S, Utsubo-Kuniyoshi R, Hatake K. The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations. Blood Cancer J. 2011;1:e15.

    PubMed  CAS  Google Scholar 

  10. Mossner E, Brunker P, Moser S, Puntener U, Schidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umana P. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2009;115:4393–4402.

    Google Scholar 

  11. Dijoseph JF, Dougher MM, Armellino DC, Evans DY, Damle NK. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia. 2007;21:2240–5.

    PubMed  CAS  Google Scholar 

  12. Beers SA, French RR, Chan HT, Lim SH, Jarrett TC, Vidal RM, Wijayaweera SS, Dixon SV, Kim H, Cox KL, Kerr JP, Johnston DA, Johnson PW, Verbeek JS, Glennie MJ, Cragg MS. Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood. 2010;115:5191–201.

    PubMed  CAS  Google Scholar 

  13. Beum PV, Kennedy AD, Williams ME, Lindorfer MA, Taylor RP. The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes. J Immunol. 2006;176:2600–9.

    PubMed  CAS  Google Scholar 

  14. Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, Hernandez-Illizaliturri FJ. Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res. 2008;14:1561–70.

    PubMed  CAS  Google Scholar 

  15. Sarro SM, Unruh TL, Zuccolo J, Sanyal R, Luider JM, Auer-Grzesiak IA, Mansoor A, Deans JP. Quantification of CD20 mRNA and protein levels in chronic lymphocytic leukemia suggests a post-transcriptional defect. Leuk Res. 2010;34:1670–3.

    PubMed  CAS  Google Scholar 

  16. Winiarska M, Bil J, Wilczek E, Wilczynski GM, Lekka M, Engelberts PJ, Mackus WJ, Gorska E, Bojarski L, Stoklosa T, Nowis D, Kurzaj Z, Makowski M, Glodkowska E, Issat T, Mrowka P, Lasek W, Dabrowska-Iwanicka A, Basak GW, Wasik M, Warzocha K, Sinski M, Gaciong Z, Jakobisiak M, Parren PW, Golab J. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med. 2008;5:e64.

    PubMed  Google Scholar 

  17. Meyer zum Buschenfelde C, Feuerstacke Y, Gotze KS, Scholze K, Peschel C. GM1 expression of non-Hodgkin’s lymphoma determines susceptibility to rituximab treatment. Cancer Res. 2008;68:5414–22.

    PubMed  Google Scholar 

  18. Wojciechowski W, Li H, Marshall S, Dell’Agnola C, Espinoza-Delgado I. Enhanced expression of CD20 in human tumor B cells is controlled through ERK-dependent mechanisms. J Immunol. 2005;174:7859–68.

    PubMed  CAS  Google Scholar 

  19. Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, Kiyoi H, Kinoshita T, Naoe T. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood. 2009;113:4885–93.

    PubMed  CAS  Google Scholar 

  20. Fischer L, Penack O, Gentilini C, Nogai A, Muessig A, Thiel E, Uharek L. The anti-lymphoma effect of antibody-mediated immunotherapy is based on an increased degranulation of peripheral blood natural killer (NK) cells. Exp Hematol. 2006;34:753–9.

    PubMed  CAS  Google Scholar 

  21. Wang SY, Racila E, Taylor RP, Weiner GJ. NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement. Blood. 2008;111:1456–63.

    PubMed  CAS  Google Scholar 

  22. Hernandez-Ilizaliturri FJ, Jupudy V, Ostberg J, Oflazoglu E, Huberman A, Repasky E, Czuczman MS. Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin’s lymphoma severe combined immunodeficiency mouse model. Clin Cancer Res. 2003;9:5866–73.

    PubMed  CAS  Google Scholar 

  23. Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, Botto M, Introna M, Golay J. Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol. 2003;171:1581–7.

    PubMed  Google Scholar 

  24. Golay J, Cittera E, Di Gaetano N, Manganini M, Mosca M, Nebuloni M, van Rooijen N, Vago L, Introna M. The role of complement in the therapeutic activity of rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica. 2006;91:176–83.

    PubMed  CAS  Google Scholar 

  25. Zhou X, Hu W, Qin X. The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy. Oncologist. 2008;13:954–66.

    PubMed  CAS  Google Scholar 

  26. Racila E, Link BK, Weng WK, Witzig TE, Ansell S, Maurer MJ, Huang J, Dahle C, Halwani A, Levy R. A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clin Cancer Res. 2008;14:6697–703.

    PubMed  CAS  Google Scholar 

  27. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95:3900–8.

    PubMed  CAS  Google Scholar 

  28. Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001;98:3383–9.

    PubMed  CAS  Google Scholar 

  29. Bellosillo B, Villamor N, Lopez-Guillermo A, Marce S, Esteve J, Campo E, Colomer D, Montserrat E. Complement-mediated cell death induced by rituximab in B-cell lymphoproliferative disorders is mediated in vitro by a caspase-independent mechanism involving the generation of reactive oxygen species. Blood. 2001;98:2771–7.

    PubMed  CAS  Google Scholar 

  30. Klepfish A, Gilles L, Ioannis K, Rachmilewitz EA, Schattner A. Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions & clinical results in refractory CLL. Ann NY Acad Sci. 2009;1173:865–73.

    PubMed  CAS  Google Scholar 

  31. Xu W, Miao KR, Zhu DX, Fang C, Zhu HY, Dong HJ, Wang DM, Wu YJ, Qiao C, Li JY. Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia. Int J Cancer. 2011;128:2192–201.

    PubMed  CAS  Google Scholar 

  32. Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, Tedder TF. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004;199:1659–69.

    PubMed  CAS  Google Scholar 

  33. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–7.

    PubMed  CAS  Google Scholar 

  34. Lim SH, Vaughan AT, Ashton-Key M, Williams EL, Dixon SV, Chan HT, Beers SA, French RR, Cox KL, Davies AJ, Potter KN, Mockridge CI, Oscier DG, Johnson PW, Cragg MS, Glennie MJ. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood. 2011;118:2530–40.

    PubMed  Google Scholar 

  35. Gluck WL, Hurst D, Yuen A, Levine AM, Dayton MA, Gockerman JP, Lucas J, Denis-Mize K, Tong B, Navid D, Difrancesco A, Milan S, Wilson SE, Wolin M. Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin Cancer Res. 2004;10:2253–64.

    PubMed  CAS  Google Scholar 

  36. Cartron G, Zhao-Yang L, Baudard M, Kanouni T, Rouille V, Quittet P, Klein B, Rossi JF. Granulocyte-macrophage colony-stimulating factor potentiates rituximab in patients with relapsed follicular lymphoma: results of a phase II study. J Clin Oncol. 2008;26:2725–31.

    PubMed  CAS  Google Scholar 

  37. Zent CS, Wu W, Bowen DA, Hanson CA, Pettinger AM, Shanafelt TD, Kay NE, Leis JF, Call TG. Addition of granulocyte macrophage colony stimulating factor does not improve response to early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Leuk Lymphoma. 2013;54:476–82.

    Google Scholar 

  38. Askew D, Chu RS, Krieg AM, Harding CV. CpG DNA induces maturation of dendritic cells with distinct effects on nascent and recycling MHC-II antigen-processing mechanisms. J Immunol. 2000;165:6889–95.

    PubMed  CAS  Google Scholar 

  39. Zent CS, Smith BJ, Ballas ZK, Wooldridge JE, Link BK, Call TG, Shanafelt TD, Bowen DA, Kay NE, Witzig TE, Weiner GJ. Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma. 2011;53:211–7.

    PubMed  Google Scholar 

  40. Hacker G, Redecke V, Hacker H. Activation of the immune system by bacterial CpG-DNA. Immunology. 2002;105:245–51.

    PubMed  CAS  Google Scholar 

  41. Jazirehi AR, Vega MI, Bonavida B. Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res. 2007;67:1270–81.

    PubMed  CAS  Google Scholar 

  42. Vega MI, Jazirehi AR, Huerta-Yepez S, Bonavida B. Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin’s lymphoma cell line via inhibition of NF-kappa B activity: role of YY1 and Bcl-xL in Fas resistance and chemoresistance, respectively. J Immunol. 2005;175:2174–83.

    PubMed  CAS  Google Scholar 

  43. Suzuki E, Umezawa K, Bonavida B. Rituximab inhibits the constitutively activated PI3 K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis. Oncogene. 2007;26:6184–93.

    PubMed  CAS  Google Scholar 

  44. Tomita A, Hiraga J, Kiyoi H, Ninomiya M, Sugimoto T, Ito M, Kinoshita T, Naoe T. Epigenetic regulation of CD20 protein expression in a novel B-cell lymphoma cell line, RRBL1, established from a patient treated repeatedly with rituximab-containing chemotherapy. Int J Hematol. 2007;86:49–57.

    PubMed  CAS  Google Scholar 

  45. Olejniczak SH, Hernandez-Ilizaliturri FJ, Clements JL, Czuczman MS. Acquired resistance to rituximab is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clin Cancer Res. 2008;14:1550–60.

    PubMed  CAS  Google Scholar 

  46. Dalle S, Dupire S, Brunet-Manguat S, Reslan L, Plesa A, Dumontet C. In vivo model of follicular lymphoma resistant to rituximab. Clin Cancer Res. 2009;15:851–7.

    PubMed  CAS  Google Scholar 

  47. Wanner K, Hipp S, Oelsner M, Ringshausen I, Bogner C, Peschel C, Decker T. Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol. 2006;134:475–84.

    PubMed  CAS  Google Scholar 

  48. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3 K/Akt pathway in cancer. Oncogene. 2008;27:5511–26.

    PubMed  CAS  Google Scholar 

  49. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature. 2005;435:677–81.

    PubMed  CAS  Google Scholar 

  50. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375–88.

    PubMed  CAS  Google Scholar 

  51. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–99.

    PubMed  Google Scholar 

  52. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–8.

    PubMed  CAS  Google Scholar 

  53. Ackler S, Xiao Y, Mitten MJ, Foster K, Oleksijew A, Refici M, Schlessinger S, Wang B, Chemburkar SR, Bauch J, Tse C, Frost DJ, Fesik SW, Rosenberg SH, Elmore SW, Shoemaker AR. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008;7:3265–74.

    PubMed  CAS  Google Scholar 

  54. Pro B, Leber B, Smith M, Fayad L, Romaguera J, Hagemeister F, Rodriguez A, McLaughlin P, Samaniego F, Zwiebel J, Lopez A, Kwak L, Younes A. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol. 2008;143:355–60.

    PubMed  CAS  Google Scholar 

  55. Ramanarayanan J, Hernandez-Ilizaliturri FJ, Chanan-Khan A, Czuczman MS. Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumor activity of rituximab. Br J Haematol. 2004;127:519–30.

    PubMed  CAS  Google Scholar 

  56. Maddipatla S, Hernandez-Ilizaliturri FJ, Knight J, Czuczman MS. Augmented antitumor activity against B-cell lymphoma by a combination of monoclonal antibodies targeting TRAIL-R1 and CD20. Clin Cancer Res. 2007;13:4556–64.

    PubMed  CAS  Google Scholar 

  57. Daniel D, Yang B, Lawrence DA, Totpal K, Balter I, Lee WP, Gogineni A, Cole MJ, Yee SF, Ross S, Ashkenazi A. Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood. 2007;110:4037–46.

    PubMed  CAS  Google Scholar 

  58. Stel AJ, Ten Cate B, Jacobs S, Kok JW, Spierings DC, Dondorff M, Helfrich W, Kluin-Nelemans HC, de Leij LF, Withoff S, Kroesen BJ. Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J Immunol. 2007;178:2287–95.

    PubMed  CAS  Google Scholar 

  59. Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL. LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12:773–84.

    PubMed  CAS  Google Scholar 

  60. Czuczman MS, Gregory SA. The future of CD20 monoclonal antibody therapy in B-cell malignancies. Leuk Lymphoma. 2010;51:983–94.

    PubMed  CAS  Google Scholar 

  61. Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2010;117:2993–3001.

    Google Scholar 

  62. Hagenbeek A, Gadeberg O, Johnson P, Pedersen LM, Walewski J, Hellmann A, Link BK, Robak T, Wojtukiewicz M, Pfreundschuh M, Kneba M, Engert A, Sonneveld P, Flensburg M, Petersen J, Losic N, Radford J. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008;111:5486–95.

    PubMed  CAS  Google Scholar 

  63. Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012;119:5126–32.

    PubMed  CAS  Google Scholar 

  64. Sehn LH, Assouline SE, Stewart DA, Mangel J, Gascoyne RD, Fine G, Frances-Lasserre S, Carlile DJ, Crump M. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood. 2012;119:5118–25.

    PubMed  CAS  Google Scholar 

  65. Morschhauser F, Marlton P, Vitolo U, Lindén O, Seymour JF, Crump M, Coiffier B, Foà R, Wassner E, Burger HU, Brennan B, Mendila M. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol. 2010;21:1870–6.

    PubMed  CAS  Google Scholar 

  66. Vugmeyster Y, Beyer J, Howell K, Combs D, Fielder P, Yang J, Qureshi F, Sandlund B, Kawaguchi L, Dummer W, Lowman H, McKeever K. Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis. J Immunother. 2005;28:212–9.

    PubMed  CAS  Google Scholar 

  67. Goldenberg DM, Rossi EA, Stein R, Cardillo TM, Czuczman MS, Hernandez-Ilizaliturri FJ, Hansen HJ, Chang CH. Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood. 2009;113:1062–70.

    PubMed  CAS  Google Scholar 

  68. Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon MO, Coleman M, Schuster SJ, Dyer MJ, Horne H, Teoh N, Wegener WA, Goldenberg DM. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27:3346–53.

    PubMed  CAS  Google Scholar 

  69. Bowles JA, Wang SY, Link BK, Allan B, Beuerlein G, Campbell MA, Marquis D, Ondek B, Wooldridge JE, Smith BJ, Breitmeyer JB, Weiner GJ. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood. 2006;108:2648–54.

    PubMed  CAS  Google Scholar 

  70. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    PubMed  CAS  Google Scholar 

  71. Klapper LN, Waterman H, Sela M, Yarden Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res. 2000;60:3384–8.

    PubMed  CAS  Google Scholar 

  72. Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27:5838–47.

    PubMed  CAS  Google Scholar 

  73. Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, Castiglioni F, Villani L, Magalotti C, Gibelli N, Oliviero B, Ballardini B, Da Prada G, Zambelli A, Costa A. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10:5650–5.

    PubMed  CAS  Google Scholar 

  74. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, Laccabue D, Zerbini A, Camisa R, Bisagni G, Neri TM, Ardizzoni A. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26:1789–96.

    PubMed  CAS  Google Scholar 

  75. Jung M, Koo JS, Moon YW, Park BW, Kim SI, Park S, Lee SH, Hong S, Rha SY, Chung HC, Kim JH, Sohn J. Overexpression of class III beta tubulin and amplified HER2 gene predict good response to paclitaxel and trastuzumab therapy. PLoS ONE. 2012;7:e45127.

    PubMed  CAS  Google Scholar 

  76. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX. Ligand-independent HER2/HER3/PI3 K complex is disrupted by trastuzumab and is effectively inhibited by the PI3 K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40.

    PubMed  CAS  Google Scholar 

  77. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 2011;17:461–9.

    PubMed  Google Scholar 

  78. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71:1515–9.

    PubMed  CAS  Google Scholar 

  79. Nagy P, Friedländer E, Tanner M, Kapanen AI, Carraway KL, Isola J, Jovin TM. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 2005;65:473–82.

    PubMed  CAS  Google Scholar 

  80. Fessler SP, Wotkowicz MT, Mahanta SK, Bamdad C. MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res Treat. 2009;118:113–24.

    PubMed  CAS  Google Scholar 

  81. Sperinde J, Jin X, Banerjee J, Penuel E, Saha A, Diedrich G, Huang W, Leitzel K, Weidler J, Ali SM, Fuchs EM, Singer CF, Köstler WJ, Bates M, Parry G, Winslow J, Lipton A. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res. 2010;16:4226–35.

    PubMed  CAS  Google Scholar 

  82. Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.

    PubMed  CAS  Google Scholar 

  83. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21:6255–63.

    PubMed  CAS  Google Scholar 

  84. Scaltriti M, Chandarlapaty S, Prudkin L, Aura C, Jimenez J, Angelini PD, Sánchez G, Guzman M, Parra JL, Ellis C, Gagnon R, Koehler M, Gomez H, Geyer C, Cameron D, Arribas J, Rosen N, Baselga J. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res. 2010;16:2688–95.

    PubMed  CAS  Google Scholar 

  85. Burstein HJ, Storniolo AM, Franco S, Forster J, Stein S, Rubin S, Salazar VM, Blackwell KL. A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol. 2008;19:1068–74.

    PubMed  CAS  Google Scholar 

  86. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the PI3 K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.

    PubMed  CAS  Google Scholar 

  87. Kataoka Y, et al. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21:255–62.

    Google Scholar 

  88. Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, Pectasides D, Kalogeras KT, Skarlos D, Fountzilas G. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447–56.

    PubMed  CAS  Google Scholar 

  89. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nuñez R, Hortobagyi GN, Yu D, Esteva FJ. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011;29:3126–32.

    PubMed  CAS  Google Scholar 

  90. Wong AL, Lee SC. Mechanisms of resistance to trastuzumab and novel therapeutic strategies in HER2-positive breast cancer. Int J Breast Cancer. 2012;2012:415170.

    PubMed  Google Scholar 

  91. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341–9.

    PubMed  CAS  Google Scholar 

  92. Yee D. Insulin-like growth factor receptor inhibitors: baby or the bathwater? J Natl Cancer Inst. 2012;104:975–81.

    PubMed  CAS  Google Scholar 

  93. Atzori F, Tabernero J, Cervantes A, Prudkin L, Andreu J, Rodríguez-Braun E, Domingo A, Guijarro J, Gamez C, Rodon J, Di Cosimo S, Brown H, Clark J, Hardwick JS, Beckman RA, Hanley WD, Hsu K, Calvo E, Roselló S, Langdon RB, Baselga J. A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17:6304–12.

    PubMed  CAS  Google Scholar 

  94. Tolcher AW, Sarantopoulos J, Patnaik A, Papadopoulos K, Lin CC, Rodon J, Murphy B, Roth B, McCaffery I, Gorski KS, Kaiser B, Zhu M, Deng H, Friberg G,Puzanov I. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol. 2009;27:5800–7.

    Google Scholar 

  95. Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev. 2012;38:292–302.

    PubMed  CAS  Google Scholar 

  96. Ekman S, Frödin JE, Harmenberg J, Bergman A, Hedlund A, Dahg P, Alvfors C, Ståhl B, Bergström S, Bergqvist M. Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 2011;50:441–7.

    PubMed  CAS  Google Scholar 

  97. Anastasi S, Sala G, Huiping C, Caprini E, Russo G, Iacovelli S, Lucini F, Ingvarsson S, Segatto O. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene. 2005;24:4540–8.

    PubMed  CAS  Google Scholar 

  98. Belkhiri A, Dar AA, Peng DF, Razvi MH, Rinehart C, Arteaga CL, El-Rifai W. Expression of t-DARPP mediates trastuzumab resistance in breast cancer cells. Clin Cancer Res. 2008;14:4564–71.

    PubMed  CAS  Google Scholar 

  99. Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G, Yang CY, Li Y, Li X, Chen CT, Mills GB, Hortobagyi GN, Mendelsohn J, Hung MC, Fan Z. Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell. 2010;18:423–35.

    PubMed  CAS  Google Scholar 

  100. Shattuck DL, Miller JK, Carraway KL 3rd, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 2008;68:1471–7.

    PubMed  CAS  Google Scholar 

  101. Agarwal S, Zerillo C, Kolmakova J, Christensen JG, Harris LN, Rimm DL, Digiovanna MP, Stern DF. Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells. Br J Cancer. 2009;100:941–9.

    PubMed  CAS  Google Scholar 

  102. Rosen LS, Senzer N, Mekhail T, Ganapathi R, Chai F, Savage RE, Waghorne C, Abbadessa G, Schwartz B, Dreicer R. A phase I dose-escalation study of Tivantinib (ARQ 197) in adult patients with metastatic solid tumors. Clin Cancer Res. 2011;17:7754–64.

    PubMed  CAS  Google Scholar 

  103. Spigel DR, et al. Final efficacy results from OAM4558 g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol. 2011;29 (suppl) Abstract 7505.

    Google Scholar 

  104. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res. 2009;69:2191–4.

    PubMed  CAS  Google Scholar 

  105. Sendur MA, Aksoy S, Altundag K. Pertuzumab in HER2-positive breast cancer. Curr Med Res Opin. 2012;28:1709–16.

    PubMed  CAS  Google Scholar 

  106. Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol. 2009;10:1179–87.

    PubMed  CAS  Google Scholar 

  107. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26:1810–6.

    PubMed  CAS  Google Scholar 

  108. Yu HA, Riely GJ. Who should receive EGFR tyrosine-kinase inhibitors? Lancet Oncol. 2012;13:1074–6.

    PubMed  Google Scholar 

  109. Mullen TD, Hannun YA, Obeid LM. Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J. 2012;441:789–802.

    PubMed  CAS  Google Scholar 

  110. Katz J, Janik JE, Younes A. Brentuximab vedotin (SGN-35). Clin Cancer Res. 2011;17:6428–36.

    PubMed  CAS  Google Scholar 

  111. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812–21.

    PubMed  CAS  Google Scholar 

  112. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blättler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.

    Google Scholar 

  113. Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398–405.

    PubMed  CAS  Google Scholar 

  114. Hurvitz SA, Kakkar R. The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies. Ther Adv Med Oncol. 2012;4:235–45.

    PubMed  Google Scholar 

  115. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol. 2003;21:2787–99.

    PubMed  CAS  Google Scholar 

  116. Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33:369–85.

    PubMed  CAS  Google Scholar 

  117. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol. 2011;13:506–13.

    Google Scholar 

  118. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    PubMed  CAS  Google Scholar 

  119. Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, Iqbal S, Groshen S, Lenz HJ. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007;25:3712–8.

    PubMed  CAS  Google Scholar 

  120. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.

    PubMed  CAS  Google Scholar 

  121. Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6:519–27.

    PubMed  CAS  Google Scholar 

  122. Sartore-Bianchi A, Bencardino K, Cassingena A, Venturini F, Funaioli C, Cipani T, Amatu A, Pietrogiovanna L, Schiavo R, Di Nicolantonio F, Artale S, Bardelli A, Siena S. Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer. Cancer Treat Rev. 2010;36(Suppl 3):S1–5.

    PubMed  CAS  Google Scholar 

  123. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.

    PubMed  Google Scholar 

  124. Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, O’Brien C, Modrusan Z, Seshagiri S, Lackner M, Stern H, Choo E, Murray L, Friedman LS, Belvin M. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009;69:3042–51.

    PubMed  CAS  Google Scholar 

  125. Kopetz S, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28(suppl):3534.

    Google Scholar 

  126. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Seshagiri S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:1445.

    CAS  Google Scholar 

  127. Saif MW, Kaley K, Chu E, Copur MS. Safety and efficacy of panitumumab therapy after progression with cetuximab: experience at two institutions. Clin Colorectal Cancer. 2010;9:315–8.

    PubMed  CAS  Google Scholar 

  128. Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, Bertario L, Leo E, Pierotti MA, Pilotti S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20:84–90.

    PubMed  CAS  Google Scholar 

  129. Kim SM, Kim JS, Kim JH, Yun CO, Kim EM, Kim HK, Solca F, Choi SY, Cho BC. Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett. 2010;296:150–9.

    PubMed  CAS  Google Scholar 

  130. Ciardiello F, Bianco R, Caputo R, Caputo R, Damiano V, Troiani T, Melisi D, De Vita F, De Placido S, Bianco AR, Tortora G. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res. 2004;10:784–93.

    PubMed  CAS  Google Scholar 

  131. Bianco R, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, Tarallo V, De Falco S, Melisi D, Benelli R, Albini A, Ryan A, Ciardiello F, Tortora G. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res. 2008;14:5069–80.

    PubMed  CAS  Google Scholar 

  132. Kies M, Gibson M, Kim S. Cetuximab (C) and bevacizumab (B) in patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN). An interim analysis. J Clin Oncol. 2008;26(15S):6072.

    Google Scholar 

  133. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PM. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27:3944–56.

    PubMed  CAS  Google Scholar 

  134. Lu Y, Li X, Liang K, Luwor R, Siddik ZH, Mills GB, Mendelsohn J, Fan Z. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res. 2007;67:8240–7.

    PubMed  CAS  Google Scholar 

  135. Kamath AV, Lu D, Gupta P, Jin D, Xiang H, Wong A, Leddy C, Crocker L, Schaefer G, Sliwkowski MX, Damico-Beyer LA. Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose. Cancer Chemother Pharmacol. 2012;69:1063–9.

    PubMed  CAS  Google Scholar 

  136. Huang S, Li C, Sliwkowski M. MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR inhibitors in head and neck and lung tumors. In: 102nd American association for cancer research, Orlando (Abstract 637).

    Google Scholar 

  137. Benavente S, Huang S, Armstrong EA, Chi A, Hsu KT, Wheeler DL, Harari PM. Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells. Clin Cancer Res. 2009;15:1585–92.

    PubMed  CAS  Google Scholar 

Download references

Conflicts of Interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Université Lyon, F-69000, Lyon, France

    Lina Reslan & Charles Dumontet

  2. Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France

    Lina Reslan & Charles Dumontet

  3. CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France

    Lina Reslan & Charles Dumontet

  4. Hospices Civils de Lyon, F-69003, Lyon, France

    Lina Reslan & Charles Dumontet

  5. INSERM 590, Faculté Rockefeller, 8 avenue Rockefeller, 69008, Lyon, France

    Charles Dumontet

Authors
  1. Lina Reslan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Dumontet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles Dumontet .

Editor information

Editors and Affiliations

  1. Molecular Genetics, University of California, Los Angeles Dept. Microbiology, Immunology &, Los Angeles, California, USA

    Benjamin Bonavida

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Reslan, L., Dumontet, C. (2013). Resistance to Anticancer Antibodies: From Mechanisms to Solutions. In: Bonavida, B. (eds) Resistance to Immunotherapeutic Antibodies in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7654-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation