Medical Oncology

, 32:205 | Cite as

EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models

  • Niina Laurila
  • Jussi P. KoivunenEmail author
Short Communication


Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.


NSCLC EGFR mutant Tyrosine kinase inhibitor Acquired resistance Chemotherapy 



The study was supported by Thelma Mäkikyrö Foundation and Sigrid Juselius Foundation. We wish to thank Anne Bisi for her technical assistance.

Conflict of interest

Authors’ declare no conflict of interest.


  1. 1.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. doi: 10.1056/NEJMoa0810699.PubMedCrossRefGoogle Scholar
  2. 2.
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8. doi: 10.1056/NEJMoa0909530.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42. doi: 10.1016/S1470-2045(11)70184-X.PubMedCrossRefGoogle Scholar
  4. 4.
    Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46. doi: 10.1016/S1470-2045(11)70393-X.PubMedCrossRefGoogle Scholar
  5. 5.
    Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34. doi: 10.1200/JCO.2012.44.2806.PubMedCrossRefGoogle Scholar
  6. 6.
    Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22. doi: 10.1016/S1470-2045(13)70604-1.PubMedCrossRefGoogle Scholar
  7. 7.
    Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389–400. doi: 10.1038/nm.3388.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. doi: 10.1126/scitranslmed.3002003.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298–303. doi: 10.1158/1078-0432.CCR-11-1468.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA Jr, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7(12):1807–14. doi: 10.1097/JTO.0b013e3182745948.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(3):346–51. doi: 10.1097/JTO.0b013e31827e1f83.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Goldberg SB, Oxnard GR, Digumarthy S, Muzikansky A, Jackman DM, Lennes IT, et al. Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. Oncologist. 2013;18(11):1214–20. doi: 10.1634/theoncologist.2013-0168.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462(7276):1070–4. doi: 10.1038/nature08622.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3(12):1404–15. doi: 10.1158/2159-8290.CD-13-0314.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Lee HJ, Schaefer G, Heffron TP, Shao L, Ye X, Sideris S, et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 2013;3(2):168–81. doi: 10.1158/2159-8290.CD-12-0357.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Taube E, Jokinen E, Koivunen P, Koivunen JP. A novel treatment strategy for EGFR mutant NSCLC with T790M-mediated acquired resistance. Int J Cancer. 2012;131(4):970–9. doi: 10.1002/ijc.26461.PubMedCrossRefGoogle Scholar
  17. 17.
    Li T, Ling YH, Goldman ID, Perez-Soler R. Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res. 2007;13(11):3413–22. doi: 10.1158/1078-0432.CCR-06-2923.PubMedCrossRefGoogle Scholar
  18. 18.
    Takano T, Fukui T, Ohe Y, Tsuta K, Yamamoto S, Nokihara H, et al. EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol. 2008;26(34):5589–95. doi: 10.1200/JCO.2008.16.7254.PubMedCrossRefGoogle Scholar
  19. 19.
    Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;14(8):777–86. doi: 10.1016/S1470-2045(13)70254-7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medical Oncology and RadiotherapyOulu University HospitalOuluFinland
  2. 2.Medical Research Center OuluOulu University Hospital and University of OuluOuluFinland

Personalised recommendations