Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRAS^G12C Inhibition.

ABSTRACT:

Purpose

Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRAS^G12C 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 KRAS^G12C cell lines were treated with the KRAS^G12C 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 inhibito

SUBMITTER: Ryan MB 

PROVIDER: S-EPMC7124991 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature