PIK3CA and cancer: With respect to KRAS, PAKs are activated in KRASG12C inhibitor-resistant cancer cells, and PAK4 mediates this resistance through the activation of both the MAPK pathway and the PI3K pathway.276 The critical role of PAK4 in mediating resistance to therapy has also been described in gastric and cervical cancers resistant to chemotherapy.277 Targeting PAK4 was further shown to inhibit Ras-mediated oncogenic signaling, hence making it an attractive partner for coinhibition with KRAS.