Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models

Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation-driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRAS mutation-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRAS mutant models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1 (SCD1) displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRAS mutant cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRAS mutant but not wild-type cells. The radiosensitizing effect was notably small, especially compared with several DNA repair inhibitors. As an alternative strategy to targeting monounsaturated fatty acid metabolism, adding polyunsaturated fatty acids phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRAS mutant cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRAS mutant tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced intertumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies. See related commentary by Buchsbaum, p. 840.