KRASi-resistant cancer cells sustain proliferation through ADGRB1-mediated activation of PI3Kγ-PAK1 signaling, which drives macropinocytosis-dependent scavenging of adipocyte-derived fatty acids to fuel mitochondrial β-oxidation independently of canonical KRAS-PI3Kα signaling. This adaptive metabolic program operates across multiple KRAS-mutated cancer types, and its disruption through ADGRB1 or PI3Kγ inhibition restores KRASi sensitivity and triggers tumor regression, establishing a generalizable therapeutic strategy for overcoming KRASi resistance.

Although inhibitors of oncogenic KRAS have shown clinical efficacy, resistance to KRAS inhibition is common, and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3Kα signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3Kγ-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3Kγ signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.