1. Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer.
- Author
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Roper N, Brown AL, Wei JS, Pack S, Trindade C, Kim C, Restifo O, Gao S, Sindiri S, Mehrabadi F, El Meskini R, Ohler ZW, Maity TK, Venugopalan A, Cultraro CM, Akoth E, Padiernos E, Chen H, Kesarwala A, Smart DK, Nilubol N, Rajan A, Piotrowska Z, Xi L, Raffeld M, Panchenko AR, Sahinalp C, Hewitt S, Hoang CD, Khan J, and Guha U
- Subjects
- Adult, Aged, Aged, 80 and over, Drug Resistance, Neoplasm drug effects, ErbB Receptors genetics, Female, Genetic Heterogeneity drug effects, Humans, Male, Middle Aged, Mutation, Protein Kinase Inhibitors therapeutic use, Exome Sequencing, Young Adult, Acrylamides therapeutic use, Aniline Compounds therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Clonal Evolution drug effects, Clonal Evolution genetics, Drug Resistance, Neoplasm genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as EGFR C797S. MET amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, PD-L1, KRAS amplification, and ESR1-AKAP12, MKRN1-BRAF fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies.
- Published
- 2020
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