Targeting PI3Kα overcomes resistance to KRas^G12C inhibitors mediated by activation of EGFR and/or IGF1R

Although several KRas^G12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRas^G12C inhibitors. To explore the mechanism rendering acquired resistance to KRas^G12C inhibitors, we established a series of KRAS^G12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRAS^G12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRAS^G12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRas^G12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRas^G12C inhibitors for therapy of KRAS^G12C-mutant cancers in future clinical trials.