Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer

Catherine B. Meador, Hailing Jin, Elisa De Stanchina, Caroline A. Nebhan, Valentina Pirazzoli, Lu Wang, Pengcheng Lu, Huy Vuong, Katherine E. Hutchinson, Peilin Jia, Xi Chen, Rosana Eisenberg, Marc Ladanyi, Katerina Politi, Zhongming Zhao, Christine M. Lovly, Darren A.E. Cross, William Pao

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefi tinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefi tinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as fi rst-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.

Original languageEnglish (US)
Pages (from-to)542-552
Number of pages11
JournalMolecular cancer therapeutics
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer'. Together they form a unique fingerprint.

  • Cite this

    Meador, C. B., Jin, H., De Stanchina, E., Nebhan, C. A., Pirazzoli, V., Wang, L., Lu, P., Vuong, H., Hutchinson, K. E., Jia, P., Chen, X., Eisenberg, R., Ladanyi, M., Politi, K., Zhao, Z., Lovly, C. M., Cross, D. A. E., & Pao, W. (2015). Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Molecular cancer therapeutics, 14(2), 542-552. https://doi.org/10.1158/1535-7163.MCT-14-0723