Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition

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 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRAS^G12C 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 KRAS^G12C inhibition in the majority of KRAS^G12C 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 KRAS^G12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to Ras, abrogated feedback reactivation more universally, and combined KRAS^G12C/SHP2 inhibition drove sustained Ras pathway suppression and improved efficacy in vitro and in vivo.

Conclusions: These data identify feedback reactivation of wild-type Ras as a key mechanism of adaptive resistance to KRAS^G12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRAS^G12C inhibitors.See related commentary by Yaeger and Solit, p. 1538.