Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.

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

Effects of PUFAs on NCI-H1703 3D tumorspheres with mutant (mut) or wild-type (wt) KRAS.

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

Fatty acid metabolism and KRAS status

Fatty acid metabolism and KRAS status.