1. Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor
- Author
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Chris Karlovich, Joel W. Neal, Andrew R. Allen, A. John Iafrate, Anuj Kalsy, Elizabeth L. Lockerman, Heather A. Wakelee, Dora Dias-Santagata, Angel R. Garcia, Aaron N. Hata, Hillary E. Mulvey, Subba R. Digumarthy, Alona Muzikansky, Linnea Fulton, Lecia V. Sequist, Richard H. DiCecca, Mitch Raponi, Mari Mino-Kenudson, Jeffrey A. Engelman, Matthew J. Niederst, Melissa Parks, Zofia Piotrowska, and Alice T. Shaw
- Subjects
Lung Neoplasms ,Drug resistance ,Biology ,Article ,Genetic Heterogeneity ,T790M ,Cell Line, Tumor ,Biopsy ,medicine ,Humans ,Neoplasm ,Prospective Studies ,Rociletinib ,Protein Kinase Inhibitors ,EGFR inhibitors ,Acrylamides ,medicine.diagnostic_test ,Genetic heterogeneity ,Gene Amplification ,DNA, Neoplasm ,medicine.disease ,Small Cell Lung Carcinoma ,respiratory tract diseases ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Pyrimidines ,Oncology ,Drug Resistance, Neoplasm ,Mutation ,Immunology ,Cancer research ,EGFR Activating Mutation - Abstract
Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790–wild-type rociletinib-resistant biopsies. Two T790–wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790–wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790–wild-type clones are required. Significance: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790–wild-type upon progression, suggesting that T790–wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713–22. ©2015 AACR. See related commentary by Ichihara and Lovly, p. 694. This article is highlighted in the In This Issue feature, p. 681
- Published
- 2015
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