Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer

Abstract

Highlights d Two or more subclonal genomic alterations are acquired upon osimertinib resistance d 66% of first-line osimertinib-treated patients acquire MET amplification d Acquired focal copy-number alterations are associated with early progression d Neuroendocrine differentiation with NSCLC histology is revealed by RNA-seq analysis

The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)

“… 48 , 49 These findings suggest that KRAS-dependent and -independent NSCLCs should be therapeutically approached as distinct subtypes since they are driven by different signaling cascades. 50 Although KRAS amplification can occur concurrently with EGFR amplification, 51 KRAS mutations tend to occur independently of EGFR mutations in NSCLC and do not respond to EGFR TKIs, as highlighted by their contrasting clinical characteristics. 52 , 53 , 54 , 55 Like other important NSCLC driver oncogenes such as EGFR and ALK, co-mutations with KRAS are quite frequent.…”

Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

“…Furthmore, the resistant cells serve as a valid model system for patients who undergo osimertinib treatment, and eventually develop resistance. We and others have primarily used genomic strategies to investigate mechanisms of osimertinib resistance ( 9, 11-15 ). To our knowledge, this is the first study to identify and compare resistance mechanism of these 3 rd generation EGFR TKIs by utilizing unbiased global proteome and phosphoproteome modification data.…”

“…Complete responses are rare, and all patients eventually develop resistance, suggesting primary and acquired resistance mechanisms decrease the efficacy of the drugs ( 9, 10 ). Genomic approaches have been used primarily to interrogate osimertinib resistance mechanisms ( 9, 11-15 ). Several mechanisms of osimertinib resistance have been identified ( 16 ), including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events ( 17 ).…”

Molecular predictors of EGFR-mutant NSCLC transformation into LCNEC after frontline osimertinib: digging under the surface

“…Recent data indicate that intrinsic heterogeneity and pre-existent subclones might predict the main mechanism(s) leading to osimertinib resistance at later timepoint. 5 In this specific case, we might speculate that a subclonal cell population harboring molecular biomarkers of neuroendocrine differentiation present at the baseline and not detectable upon conventional histological examination, underwent progressive clonal evolution under the selective pressure of EGFR TKI treatment, finally leading to a pathological transition towards high-grade LCNEC. Baseline molecular heterogeneity, particularly the presence of molecular stigmata of potential transformation into high-grade neuroendocrine carcinoma ( TP53 and RB1 alterations), might support the upfront application of broad, NGS-based, genomic profiling and would constitute a potential biological rationale for treatments combining chemotherapy and EGFR TKIs in such cases.…”