Fatty acid scavenging enables cancer escape from KRAS inhibition

Although inhibitors of oncogenic KRAS have shown clinical efficacy1, resistance to KRAS inhibition is common2, 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-PI3Kγ; 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.