PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib

BACKGROUND: KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRAS(G12C) mutant have reported promising results. However, primary and acquired resistance may limit their clinical use. METHODS: Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance. RESULTS: The resistant cells exhibited increased cell-matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX486 in synergy with sotorasib reduced the viability of KRAS(G12C) mutant cancer cells. Furthermore, the PI3K/AKT pathway was constitutively active in sotorasib-resistant cells. The overexpression of constitutively activated PI3K or the knockdown of PTEN resulted in resistance to sotorasib. PI3K inhibitor alpelisib was synergistic with sotorasib in compromising the viability of KRAS(G12C) mutant cancer cells. Moreover, PI3K and PAK pathways formed a mutual positive regulatory loop that mediated sotorasib resistance. CONCLUSIONS: Our results indicate that the cell-matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways.