Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition

作者：Meagan B. Ryan, Ferran Fece de la Cruz, Sarah Phat, David T. Myers, Edmond Wong, Heather A. Shahzade, Catriona B. Hong, Ryan B. Corcoran · 发表于：Clinical Cancer Research · 年份：2019 · DOI：10.1158/1078-0432.ccr-19-3523 · 被引用次数：512 · 研究领域：Melanoma and MAPK Pathways、Protein Kinase Regulation and GTPase Signaling、Cytokine Signaling Pathways and Interactions

Abstract Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an “undruggable” target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design: A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRASG12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy. Results: We observed rapid adaptive RAS pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRASG12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improve...