Abstract 1114: Evaluating strategies to harness metabolic vulnerabilities in cervical

Abstract

Abstract Tumor cells frequently alter their metabolism to generate biomolecular intermediates for tumor maintenance and proliferation. Previous reports from Dr. Julie Schwarz’s laboratory have shown that cervical cancer cells with altered AKT/mTOR pathways show increased reliance on glucose and exogenous glutamine. The laboratory has introduced PIK3CA E545K mutation and PTEN null mutation in cervical cancer cell line SiHa. Further, to evaluate the role of glutamine metabolism in these genotypes, these cells were cultured in sequentially lower levels of glutamine until these cells were able to proliferate without exogenous glutamine supplementation. These isogenic long-term glutamine-deprived (QD) cells allow us to tease out the role of these specific mutations in cellular metabolism. In our study, long-term glutamine deprivation inhibits the proliferation of rapidly proliferating PI3K-AKT-altered cell lines. Even though glutamine is required for GSH synthesis, which quenches reactive oxygen species, QD cells were refractory to cisplatin and irradiation. Since PI3K-AKT altered were dependent on exogenous glutamine, it was expected that QD cells would have lower GLS levels to inhibit glutaminolysis. However, GLS levels in WT and QD were similar. Altogether, these data indicate that in PI3K-AKT altered cervical tumor glutamine antagonists can reduce tumor proliferation. Further glutamine reduction does not alter GLS levels and hence GLS can be targeted as well to further improve treatment outcomes. To evaluate the alternate metabolic dependencies in cervical cancer tumors, both cellular as well as secreted metabolites were evaluated. To identify alternative pathways that are activated in these glutamine-deprived cell lines, we cultured these cells in uniformly labeled 13C glucose. Mass spectrometric studies also evaluated the protein levels of various metabolic intermediates in glutamine-deprived cell lines compared to control cells. To confirm our observations, we used kit-based assays to evaluate metabolites in the cells. To further confirm the change in the metabolite pathway we evaluated changes in transcriptional changes of regulating proteins/enzymes. This pre-clinical study reinforced efforts that are anticipated to reveal new metabolic vulnerabilities of cancer cells that can be targeted by therapeutic interventions. This study also helped us evaluate druggable metabolic targets that can be targeted for effective tumor eradication along with conventional treatment. This understanding will help advance the pre-clinical trials persistent to the cure of cervical cancer. Citation Format: Dr Julie K. Schwarz, Dr Nishanth Gabriel, Aunannya Banik. Evaluating strategies to harness metabolic vulnerabilities in cervical [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1114.