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Targeting the CDK4/6 Pathway in Breast Cancer

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Breast Cancer

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Abstract

CDK4 and 6 are central regulators of cell cycle entry. The CDK4/6 pathway is frequently deregulated in breast cancer, and strategies to target this pathway have recently been proven to be effective in breast cancer patients. Preclinical and clinical data suggest that CDK4/6 inhibitors might be particularly useful in patients with hormone receptor-positive or HER2-positive tumors, while the role of such inhibitors in triple-negative breast cancer is still controversial.

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References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  2. Henley SA, Dick FA (2012) The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Div 7(1):10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Choi YJ, Anders L (2014) Signaling through cyclin D-dependent kinases. Oncogene 33(15):1890–1903

    Article  CAS  PubMed  Google Scholar 

  4. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11(8):558–572

    Article  CAS  PubMed  Google Scholar 

  5. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75(4):805–816

    Article  CAS  PubMed  Google Scholar 

  6. Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J (1993) Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science 260(5107):536–539

    Article  CAS  PubMed  Google Scholar 

  7. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8(1):9–22

    Article  CAS  PubMed  Google Scholar 

  8. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9(10):1149–1163

    Article  CAS  PubMed  Google Scholar 

  9. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78(1):67–74

    Article  CAS  PubMed  Google Scholar 

  10. Lukas J, Bartkova J, Bartek J (1996) Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol 16(12):6917–6925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Medema RH, Herrera RE, Lam F, Weinberg RA (1995) Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A 92(14):6289–6293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Parry D, Bates S, Mann DJ, Peters G (1995) Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J 14(3):503–511

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sherr CJ, Beach D, Shapiro GI (2015) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6(4):353–367

    Article  PubMed  PubMed Central  Google Scholar 

  14. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14(2):130–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18(22):2699–2711

    Article  CAS  PubMed  Google Scholar 

  16. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118(4):493–504

    Article  CAS  PubMed  Google Scholar 

  17. Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9(1):23–32

    Article  CAS  PubMed  Google Scholar 

  18. Reddy HK, Mettus RV, Rane SG, Grana X, Litvin J, Reddy EP (2005) Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res 65(22):10174–10178

    Article  CAS  PubMed  Google Scholar 

  19. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9(1):13–22

    Article  CAS  PubMed  Google Scholar 

  20. Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411(6841):1017–1021

    Article  CAS  PubMed  Google Scholar 

  21. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166

    Article  CAS  PubMed  Google Scholar 

  22. Pitts TM, Davis SL, Eckhardt SG, Bradshaw-Pierce EL (2014) Targeting nuclear kinases in cancer: development of cell cycle kinase inhibitors. Pharmacol Ther 142(2):258–269

    Article  CAS  PubMed  Google Scholar 

  23. Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R, Niesvizky R, Cho H, Ely S, Moore MA, Chen-Kiang S (2006) A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 66(15):7661–7667

    Article  CAS  PubMed  Google Scholar 

  24. Rivadeneira DB, Mayhew CN, Thangavel C, Sotillo E, Reed CA, Grana X, Knudsen ES (2010) Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 138(5):1920–1930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70(8):3228–3238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, Yang G, Chalukya M, Wang HJ, Anderson L, Kalli KR et al (2011) Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 17(6):1591–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Logan JE, Mostofizadeh N, Desai AJ, VON Euw E, Conklin D, Konkankit V, Hamidi H, Eckardt M, Anderson L, Chen HW, Ginther C et al (2013) PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res 33(8):2997–3004

    CAS  PubMed  Google Scholar 

  28. Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O’Dwyer PJ (2011) Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 104(12):1862–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK (2012) Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 18(2):568–576

    Article  CAS  PubMed  Google Scholar 

  30. Hu W, Sung T, Jessen BA, Thibault S, Finkelstein MB, Khan NK, Sacaan AI (2015) Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 22(8):2000–2008

    Article  PubMed  Google Scholar 

  31. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL et al (2014) Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Investig New Drugs 32(5):825–837

    Article  CAS  Google Scholar 

  32. Tate SC, Cai S, Ajamie RT, Burke T, Beckmann RP, Chan EM, De Dios A, Wishart GN, Gelbert LM, Cronier DM (2014) Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 20(14):3763–3774

    Article  CAS  PubMed  Google Scholar 

  33. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De Dios A (2015) Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos 43(9):1360–1371

    Article  CAS  PubMed  Google Scholar 

  34. Patnaik A RL, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L,, Papadopoulos KP BM, Rasco DW, Myrand SP, Kulanthaivel P, Li L, Frenzel M,, Cronier DM CE, Flaherty KT, Wen PY, Shapiro GI (2014) Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer (abstract). Proceedings of the 105th annual meeting of the American Association for Cancer Research April 5–9, 2014; San Diego, CA. Philadelphia, PA: AACR; abstract nr CT232

    Google Scholar 

  35. Goldman JWGL, Patnaik A, Rosen LS, Hilton JF, Papadopoulos KP, Tolaney SM, Beeram M, Rasco DW, Myrand SP, Beckmann RP, Kulanthaivel P, Frenzel M, Cronier D, Chan EM, Flaherty K, Wen PY, Tolcher AW, Shapiro G (2014) Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer. J Clin Oncol 32(5s):abstr 8026

    Google Scholar 

  36. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S et al (2013) Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 19(22):6173–6182

    Article  CAS  PubMed  Google Scholar 

  37. Zhang YX, Sicinska E, Czaplinski JT, Remillard SP, Moss S, Wang Y, Brain C, Loo A, Snyder EL, Demetri GD, Kim S et al (2014) Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Mol Cancer Ther 13(9):2184–2193

    Article  CAS  PubMed  Google Scholar 

  38. Eilers G, Czaplinski JT, Mayeda M, Bahri N, Tao D, Zhu M, Hornick JL, Lindeman NI, Sicinska E, Wagner AJ, Fletcher JA et al (2015) CDKN2A/p16 loss implicates CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans. Mol Cancer Ther 14(6):1346–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Infante JRSG, Witteveen P, Gerecitano JF, Ribrag V, Chugh R, Issa I, Chakraborty A, Matano A, Zhao X, Parasuraman S, Cassier P (2014) A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J Clin Oncol 32(5s):abstr 2528

    Google Scholar 

  40. Network CGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  Google Scholar 

  41. Eeckhoute J, Carroll JS, Geistlinger TR, Torres-Arzayus MI, Brown M (2006) A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes Dev 20(18):2513–2526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stender JD, Frasor J, Komm B, Chang KC, Kraus WL, Katzenellenbogen BS (2007) Estrogen-regulated gene networks in human breast cancer cells: involvement of E2F1 in the regulation of cell proliferation. Mol Endocrinol 21(9):2112–2123

    Article  CAS  PubMed  Google Scholar 

  43. Kenny FS, Hui R, Musgrove EA, Gee JM, Blamey RW, Nicholson RI, Sutherland RL, Robertson JF (1999) Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin Cancer Res 5(8):2069–2076

    CAS  PubMed  Google Scholar 

  44. McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, Henry JA, Angus B, Lennard TW, Horne CH (1995) Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11(5):885–891

    CAS  PubMed  Google Scholar 

  45. Lundgren K, Brown M, Pineda S, Cuzick J, Salter J, Zabaglo L, Howell A, Dowsett M, Landberg G, Trans AI (2012) Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res 14(2):R57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Naidu R, Wahab NA, Yadav MM, Kutty MK (2002) Expression and amplification of cyclin D1 in primary breast carcinomas: relationship with histopathological types and clinico-pathological parameters. Oncol Rep 9(2):409–416

    CAS  PubMed  Google Scholar 

  47. Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J (1996) A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer 73(6):728–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES (2011) Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18(3):333–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL (1995) Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 9(12):1804–1813

    CAS  PubMed  Google Scholar 

  51. Carroll JS, Prall OW, Musgrove EA, Sutherland RL (2000) A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence. J Biol Chem 275(49):38221–38229

    Article  CAS  PubMed  Google Scholar 

  52. Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stendahl M, Kronblad A, Ryden L, Emdin S, Bengtsson NO, Landberg G (2004) Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br J Cancer 90(10):1942–1948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jirstrom K, Stendahl M, Ryden L, Kronblad A, Bendahl PO, Stal O, Landberg G (2005) Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 65(17):8009–8016

    Article  PubMed  Google Scholar 

  55. Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, Dowsett M, Jiang A, Smith RA, Maira SM, Manning HC et al (2011) ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 1(4):338–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bosco EE, Wang Y, Xu H, Zilfou JT, Knudsen KE, Aronow BJ, Lowe SW, Knudsen ES (2007) The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J Clin Invest 117(1):218–228

    Article  CAS  PubMed  Google Scholar 

  57. Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68(3):826–833

    Article  CAS  PubMed  Google Scholar 

  58. Giessrigl B, Schmidt WM, Kalipciyan M, Jeitler M, Bilban M, Gollinger M, Krieger S, Jager W, Mader RM, Krupitza G (2013) Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. Br J Cancer 109(10):2751–2762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sanders DA, Ross-Innes CS, Beraldi D, Carroll JS, Balasubramanian S (2013) Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells. Genome Biol 14(1):R6

    Article  PubMed  PubMed Central  Google Scholar 

  60. Millour J, Constantinidou D, Stavropoulou AV, Wilson MS, Myatt SS, Kwok JM, Sivanandan K, Coombes RC, Medema RH, Hartman J, Lykkesfeldt AE et al (2010) FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance. Oncogene 29(20):2983–2995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wierstra I, Alves J (2006) Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol Chem 387(7):949–962

    CAS  PubMed  Google Scholar 

  62. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, Zhai H, Vidal M, Gygi SP, Braun P, Sicinski P (2011) A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20(5):620–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G et al (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11(5):R77

    Article  PubMed  PubMed Central  Google Scholar 

  64. Koehler M, Vanarsdale TL, Shields D, Arndt K, Yuan J, Lee N, Eisele K, Chionis J, Cao J, Painter CL (2014) 60p * mechanism of action for combined CDK4/6 and ER inhibition in ER positive breast cancer. Ann Oncol 25(Suppl 1):i21

    Article  Google Scholar 

  65. De Michele A, Amy CS, Heitjan D, Randolph S, Gallagher M, Lal P, Feldman MD, Zhang PJ, Schnader A, Zafman K, Domchek SM, Gogineni K, Keefe SM, Fox KR, O’Dwyer PJ (2013) A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer. J Clin Oncol 31(15_suppl) (May 20 Supplement, 2013 ASCO Annual Meeting Abstracts):519

    Google Scholar 

  66. Finn RS, Crown J, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk YV, Thummala AR, Voytko NL, Huang X, Kim ST, Randolph SS, Slamon D (2014) Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer. (PALOMA-1; TRIO-18) (abstract). Proceedings of the 105th annual meeting of the American Association for Cancer Research; 2014 Apr 5–9; San Diego, CA. Philadelphia, PA: AACR 2014, Abstract nr CT101

    Google Scholar 

  67. Stearns V (2016) Safety results of the US expanded access program (EAP) of palbociclib in combination with letrozole as treatment of post-menopausal women with hormone-receptor-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC) for whom letrozole therapy is deemed appropriate. Cancer Res 76(4 Suppl):P4-13-05

    Article  Google Scholar 

  68. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C et al (2015) Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373(3):209–219

    Article  CAS  PubMed  Google Scholar 

  69. Goetz MP, Beeram M, Beck T, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, Edenfield WJ, Richards DA, Turner PK et al. (2015) Abemaciclib, an inhibitor of CDK4 and 6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. San Antonio Breast Cancer Symposium, Abstract P4-13-25

    Google Scholar 

  70. Munster PN, Hamilton EP, Estevez LG, De Boer RH, Mayer IA, Campone M, Asano S, Bhansali S, Zhang V, Hewes B, Juric D (2014) Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer. J Clin Oncol 32(26_suppl):143

    Article  Google Scholar 

  71. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529

    Article  CAS  PubMed  Google Scholar 

  72. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, Lockerman EL, Pollack SF, Liu M, Li X, Lehar J et al (2014) CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26(1):136–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Juric D, Ismail-Khan R, Campone M, García-Estévez L, Becerra C, De Boer R, Hamilton E, Mayer IA, Hui R, Lathrop KI, Pagano O et al. (2015) Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2− breast cancer: safety, preliminary efficacy and molecular analysis. San Antonio breast cancer symposium, Abstract P3-14-01

    Google Scholar 

  74. Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, Weise A, Nardi L, Zhang V, Bhansali SG, Hewes B et al. (2015) Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2– advanced breast cancer. Proceedings from 2015 San Antonio breast cancer symposium

    Google Scholar 

  75. Yang C, Ionescu-Tiba V, Burns K, Gadd M, Zukerberg L, Louis DN, Sgroi D, Schmidt EV (2004) The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 164(3):1031–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Knudsen E, Cox D, Franco J, Frankel A, Haley B, Witkiewicz A (2014) 590 targeting CDK4/6 in HER2 positive breast cancer: therapeutic effect, markers, and combination strategies. Ann Oncol 25(Suppl 1):i21

    Article  Google Scholar 

  77. Witkiewicz AK, Cox D, Knudsen ES (2014) CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 5(7–8):261–272

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, Zamboni WC, Wong KK, Perou CM, Sharpless NE (2012) Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst 104(6):476–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lamb R, Lehn S, Rogerson L, Clarke RB, Landberg G (2013) Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity. Cell Cycle 12(15):2384–2394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29(28):4018–4032

    Article  CAS  PubMed  Google Scholar 

  81. Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, Knudsen ES (2012) Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 11(14):2756–2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Dean JL, McClendon AK, Knudsen ES (2012) Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem 287(34):29075–29087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. McClendon AK, Dean JL, Rivadeneira DB, Yu JE, Reed CA, Gao E, Farber JL, Force T, Koch WJ, Knudsen ES (2012) CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 11(14):2747–2755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Emerson L, Dean A, Ellis MJ (2012) Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat 136(2):503–511

    Article  CAS  PubMed  Google Scholar 

  85. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A et al (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21(11):2101–2109

    Article  CAS  PubMed  Google Scholar 

  86. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y et al (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31(16):2024–2028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS et al (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119(20):4597–4607

    Article  CAS  PubMed  Google Scholar 

  88. Herschkowitz JI, He X, Fan C, Perou CM (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES (2010) RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9(20):4153–4163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Florence, Italy

    Luca Malorni, Ilenia Migliaccio, Cristina Guarducci, Martina Bonechi & Angelo Di Leo

  2. Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Florence, Italy

    Luca Malorni, Ilenia Migliaccio & Angelo Di Leo

Authors
  1. Luca Malorni
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  2. Ilenia Migliaccio
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  3. Cristina Guarducci
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  4. Martina Bonechi
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  5. Angelo Di Leo
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Correspondence to Luca Malorni or Angelo Di Leo .

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Editors and Affiliations

  1. European Institutee of Oncology, Milan, Italy

    Umberto Veronesi

  2. European Institute of Oncology, Milan, Italy

    Aron Goldhirsch

  3. European Institute of Oncology, Milan, Italy

    Paolo Veronesi

  4. San Raffaele University and Research Hospital, Milano, Italy

    Oreste Davide Gentilini

  5. European Institute of Oncology, Milan, Italy

    Maria Cristina Leonardi

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Malorni, L., Migliaccio, I., Guarducci, C., Bonechi, M., Di Leo, A. (2017). Targeting the CDK4/6 Pathway in Breast Cancer. In: Veronesi, U., Goldhirsch, A., Veronesi, P., Gentilini, O., Leonardi, M. (eds) Breast Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-48848-6_69

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  • DOI: https://doi.org/10.1007/978-3-319-48848-6_69

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