Skip to main content

Advertisement

SpringerLink
Log in

Defining clinically relevant molecular subsets of lung cancer

  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, induce dramatic responses in certain patients with non-small cell lung cancer (NSCLC). As such, the drugs provide an unexpected tool to dissect clinically relevant molecular subsets of NSCLC. For example, using mutational profiling of tumor DNA from patients with sensitivity, primary resistance, and secondary resistance to these agents, we and others have demonstrated that somatic mutations in the tyrosine kinase domain of EGFR are associated with sensitivity to gefitinib and erlotinib, while mutations in KRAS, which encodes a GTPase downstream of EGFR, are associated with primary resistance. Furthermore, second site mutations in the EGFR kinase domain are commonly found in patients with acquired resistance. We are now using a variety of molecular and biological approaches to help further define molecular subsets of lung cancer that have relevance in the clinic.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE (2003) Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949

    Google Scholar 

  2. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PA Jr, Varella-Garcia M (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643–655

    Article  PubMed  CAS  Google Scholar 

  3. Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, Milanov ZV, Atteridge CE, Biggs WH, Edeen PT, Floyd M, Ford JM, Grotzfeld RM, Herrgard S, Insko DE, Mehta SA, Patel HK, Pao W, Sawyers CL, Varmus H, Zarrinkar PP, Lockhart DJ (2005) Inhibition of drug-resistant mutants of ABL, KIT and EGF receptor kinases. Proc Natl Acad Sci USA 102:11011–11016

    Article  PubMed  CAS  Google Scholar 

  4. Daub H, Specht K, Ullrich A (2004) Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Cancer 3:1001–1010

    Article  CAS  Google Scholar 

  5. Eberhard DJ, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, Ince WL, Janne PA, Januario T, Johnson DH, Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, Stinson JA, Zhang YR, Seshagiri S, Hillan KJ (2005) Mutations in the epidermal growth factor receptor and KRAS are predictive and prognostic indicators in non-small cell lung cancers treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900–5909

    Article  PubMed  CAS  Google Scholar 

  6. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15:3249–3262

    Article  PubMed  CAS  Google Scholar 

  7. Fujimoto N, Wislez M, Zhang J, Iwanaga K, Dackor J, Hanna AE, Kalyankrishna S, Cody DD, Price RE, Sato M, Shay JW, Minna JD, Peyton M, Tang X, Massarelli E, Herbst RS, Threadgill DW, Wistuba II, Kurie JM (2005) High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 65:11478–11485

    Article  PubMed  CAS  Google Scholar 

  8. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246

    Article  PubMed  CAS  Google Scholar 

  9. Genzyme (2005) Genzyme launches exclusive lung cancer test. (Press release.) http://www.genzyme.com

  10. Gow C-H, Shih J-Y, Chang Y-L, Yu C-J (2005) Acquired gefitinib-resistant mutation of EGFR in a chemonaive lung adenocarcinoma harboring gefitinib-sensitive mutation L858R. PLoS Med 2:e269

    Google Scholar 

  11. Greulich H, Chen T-H, Feng W, Janne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313

    Google Scholar 

  12. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349

    Article  PubMed  CAS  Google Scholar 

  13. Huang S-F, Liu H-P, Li L-H, Ku Y-C, Fu Y-N, Tsai H-Y, Chen Y-T, Lin Y-F, Chang W-C, Kuo H-P, Wu Y-C, Chen Y-R, Tsai S-F (2004) High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10:8195–8203

    Article  PubMed  CAS  Google Scholar 

  14. Jain A, Tindell CA, Laux I, Hunter JB, Curran J, Galkin A, Afar DE, Aronson N, Shak S, Natale RB, Agus DB (2005) Epithelial membrane protein-1 is a biomarker of gefitinib resistance. Proc Natl Acad Sci USA 102:11858–11863

    Article  PubMed  CAS  Google Scholar 

  15. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. New Engl J Med 352:786–792

    Article  PubMed  CAS  Google Scholar 

  16. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923

    Article  PubMed  CAS  Google Scholar 

  17. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158

    Article  PubMed  CAS  Google Scholar 

  18. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670

    Article  PubMed  CAS  Google Scholar 

  19. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  20. Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese PP, Iarussi T, Mucilli F, Mezzetti A, Cuccurullo F, Sacco R, Buttitta F (2005) EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 23:857–865

    Article  PubMed  CAS  Google Scholar 

  21. Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, Krug LM, Pao W, Rizvi N, Pizzo B, Tyson L, Venkatraman E, Ben-Porat L, Memoli N, Zakowski M, Rusch V, Heelan RT (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103–1109

    Article  PubMed  CAS  Google Scholar 

  22. Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, Hatooka S, Shinoda M, Takahashi T, Yatabe Y (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513–2520

    Article  PubMed  CAS  Google Scholar 

  23. Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, DiOrio C, Doty J, Morin MJ, Moyer MP, Neveu M, Pollack VA, Pustilnik LR, Reynolds MM, Sloan D, Theleman A, Miller P (1997) Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848

    PubMed  CAS  Google Scholar 

  24. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  25. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311

    Article  PubMed  CAS  Google Scholar 

  26. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    Google Scholar 

  27. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Landanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17

    Google Scholar 

  28. Pham D, Kris MG, Riely GJ, Sarkaria IS, McDonough T, Chuai S, Venkatraman ES, Miller VA, Ladanyi M, Pao W, Wilson RK, Singh B, Rusch VW (2006) Use of cigarette smoking history to estimate the likelihood of mutations in epidermal growth factor receptor (EGFR) exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 24:1700–1704

    Article  PubMed  CAS  Google Scholar 

  29. Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES, Zakowski MF, Kris MG, Ladanyi M, Miller VA (2006) Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12:839–844

    Article  PubMed  CAS  Google Scholar 

  30. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339–346

    Article  PubMed  CAS  Google Scholar 

  31. Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, Ichimura K, Tsuda T, Yano M, Tsukada K, Tabata M, Ueoka H, Tanimoto M, Date H, Gazdar A, Shimizu N (2005) The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 11:1167–1173

    PubMed  CAS  Google Scholar 

  32. Tsao M-S, Sakurada A, Cutz J-C, Zhu C-Q, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer—Molecular and clinical predictors of outcome. New Engl J Med 353:133–144

    Article  PubMed  CAS  Google Scholar 

  33. Ward WH, Cook PN, Slater AM, Davies DH, Holdgate GA, Green LR (1994) Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 48:659–666

    Article  PubMed  CAS  Google Scholar 

  34. Yang SH, Mechanic LE, Yang P, Landi MT, Bowman ED, Wampfler J, Meerzaman D, Hong KM, Mann F, Dracheva T, Fukuoka J, Travis W, Caporaso NE, Harris CC, Jen J (2005) Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 11:2106–2110

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author acknowledges all the members of the MSKCC Lung Cancer Oncogenome Group, the patients who consented for participation in these studies, and for funding: the Joan’s Legacy Foundation, the Doris Duke Charitable Foundation, NIH, and an anonymous donor.

Author information

Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 125, New York, NY, 10021, USA

    William Pao

  2. Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    William Pao

  3. Department of Medicine, New York Presbyterian Hospital, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA

    William Pao

Authors
  1. William Pao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William Pao.

Additional information

This work was presented at the 21st Bristol–Myers Squibb Nagoya International Cancer Treatment Symposium, “Lung Cancer: Novel Therapy against Malfunctioning Molecules”, 24–25 February 2006, Nagoya, Japan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pao, W. Defining clinically relevant molecular subsets of lung cancer. Cancer Chemother Pharmacol 58 (Suppl 1), 11–15 (2006). https://doi.org/10.1007/s00280-006-0310-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-006-0310-x

Keywords

Search

Navigation