Abstract B051: Monounsaturated fatty acids mediate sensitivity to Ras inhibitors

Abstract

Despite accounting for only 3% of annual cancer cases each year, pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related death in the United States. High mortality is driven by late diagnosis, aggressive metastasis, and broad resistance to therapy; together these features leave the five-year survival rate at only 13%. In the search for better therapies, a great deal of effort has focused on targeting KRAS, the requisite oncogene mutated almost universally in PDA. As KRAS inhibitors finally reach the clinic, they are poised to significantly improve patient outcomes followed by eventual disease relapse. Our next task will be to identify targetable molecular drivers of KRAS-independent tumor regrowth. Given the major role for KRAS in metabolic rewiring, we hypothesized that nutrient availability in the tumor might condition response to Ras inhibition by exogenously rescuing metabolic defects caused by loss of KRAS signaling. As a proof of concept, we cultured tumor explants from different tumor regions and collected the metabolic fraction from explant conditioned media. The response of pancreatic cancer organoids to Ras inhibition varied when cultured with these different metabolic fractions, suggesting that local metabolic conditions may indeed influence dependence on KRAS. Given the reliance of KRAS-mutant PDA cells on the scavenging of exogenous lipids, we hypothesized that lipid availability may be an important factor in mediating therapeutic sensitivity. Screening across lipid species revealed that the monounsaturated fatty acid (MUFA) oleic acid could rescue the proliferation of PDA cells treated with KRASG12D-specific or pan-Ras inhibitors; saturated fatty acids conversely sensitized cells to Ras therapy in vitro. Cancer cells treated with oleic acid could sustain AKT signaling when KRAS was inhibited, while treatment with PI3K, mTOR, or AKT inhibitors blocked the effect of oleic acid on viability in context of Ras inhibition. Exogenous MUFA led to remodeling of phospholipid species, suggesting that phospholipid desaturation may contribute to Ras-independent AKT signaling, possibly through direct activation of mTOR signaling via phosphatidic acid. Indeed, pharmacological inhibition of phospholipase D, an enzyme that regulates phosphatidic acid levels via phospholipid hydrolysis, reduced AKT signaling and synergized with pan-Ras inhibition. These results suggests that lipid availability, and MUFA in particular, may mediate sensitivity to Ras inhibition and serve as an important target for combination therapy.