Fatty acid scavenging enables cancer escape from KRAS inhibition
Yuan, Z.; Lin, B.; Wang, C.; Miao, Y.; Zhang, D.; Meng, Z.; Wang, G.; Lowy, A. M.; Karin, M.; Yang, F.; Sun, B.; Su, H.
Show abstract
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-PI3K signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3K{gamma}-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3K{gamma} 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.
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