Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models
Shan Lu1,2, Xiao Pan1, Eva Volckova1
1Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract:
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.
Insights
KRAS mutations drive radiation resistance in lung cancer. Targeting metabolic vulnerabilities, like SCD1, with drugs or polyunsaturated fatty acids can overcome this resistance, offering new therapeutic strategies.
Area of Science:
- Oncology
- Cancer Metabolism
- Radiation Oncology
Background:
- KRAS oncogene mutations are linked to radioresistance in tumors.
- KRAS-mutant tumors exhibit cancer stem cell (CSC)-like properties and potential metabolic vulnerabilities.
- Metabolic targeting offers a strategy to overcome CSC-associated radioresistance.
Purpose of the Study:
- To develop and utilize a 3D sphere culture system for screening radiation/drug combinations against KRAS-mutant lung cancer.
- To identify metabolic liabilities in KRAS-mutant tumors that can be targeted to enhance radiosensitization.
- To investigate the role of stearoyl-CoA desaturase-1 (SCD1) in KRAS-driven radioresistance.
Main Methods:
- Established a 3D sphere culture system under lipid-limiting conditions to promote stemness and lipogenesis.
- Screened 32 KRAS-mutant lung cancer models using this 3D screening approach.
- Investigated the effects of glutaminase inhibitor CB-839 and SCD1 inhibitors on radiosensitization in various KRAS-mutant models, including isogenic and co-mutant settings.
Main Results:
- CB-839 showed significant radiosensitization in KRAS mutant models with LKB1 co-mutations.
- SCD1 inhibition demonstrated genotype-dependent radiosensitization, with KEAP1 co-mutation and SCD1 expression as potential predictors.
- KRAS mutant cells exhibited increased SCD1 expression and a higher ratio of monounsaturated to saturated fatty acids, which was reversed by SCD1 inhibition.
- Polyunsaturated fatty acids mimicked SCD1 inhibition effects, suppressed tumor growth in vivo, and reduced CSC-like phenotypes.
Conclusions:
- A novel 3D screening platform effectively models KRAS-mutant tumors and identifies therapeutic targets.
- Targeting lipogenesis, specifically SCD1, represents a viable strategy to overcome KRAS-driven radioresistance.
- Significant intertumoral heterogeneity exists in radiation/drug responses, underscoring complex genomic dependencies in lung cancer treatment.
