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- W4361946114 abstract "<div>Abstract<p><b>Purpose:</b> To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled <i>EGFR</i>-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.</p><p><b>Experimental Design:</b> Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic <i>EGFR</i>-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by <i>in vivo</i> and <i>in vitro</i> studies.</p><p><b>Results:</b> In 200 <i>EGFR</i>-mutant pretreatment samples, the most frequent concurrent alterations were mutations in <i>TP53, PIK3CA, CTNNB1</i>, and <i>RB1</i> and focal amplifications in <i>EGFR, TTF1, MDM2, CDK4</i>, and <i>FOXA1</i>. Shorter time to progression on EGFR TKI was associated with amplification of <i>ERBB2</i> (HR = 2.4, <i>P</i> = 0.015) or <i>MET</i> (HR = 3.7, <i>P</i> = 0.019), or mutation in <i>TP53</i> (HR = 1.7, <i>P</i> = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), <i>MET</i> (7%), and <i>ERBB2</i> amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included <i>BRAF</i> fusion, <i>FGFR3</i> fusion, <i>YES1</i> amplification, <i>KEAP1</i> loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Conclusions:</b> <i>EGFR</i>-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. <i>Clin Cancer Res; 24(13); 3108–18. ©2018 AACR</i>.</p></div>" @default.
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- W4361946114 date "2023-03-31" @default.
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- W4361946114 title "Data from Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance" @default.
- W4361946114 doi "https://doi.org/10.1158/1078-0432.c.6525903" @default.
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