Abstract A007: NF1 loss of function enhances chemoresistance in high-grade serous carcinoma

Abstract High-grade serous ovarian carcinoma (HGSC) is an aggressive gynecologic malignancy that is associated with late-stage diagnosis and peritoneal metastases. Treatment options are limited to surgical resection and taxane- or platinum-based chemotherapy. While many patients initially respond favorably to chemotherapy, roughly 80% will experience a recurrence, highlighting a clinical need to study resistance mechanisms. HGSC tumors frequently harbor mutations in TP53, BRCA1/2, and NF1. Neurofibromin-1 (NF1) is a tumor suppressor that is mutated or lost in about 20% of HGSCs. NF1 most notably regulates Ras activity, and its loss is associated with increased mitogenic signaling. However, the mechanism by which NF1 loss contributes to disease progression and chemoresistance is unclear. To investigate the functional impact of NF1 loss on HGSC progression, we employed an in vivo model of metastatic disease with shRNA-mediated knockdown of NF1 (or a non-targeting control). Interestingly, NF1 knockdown induces chemoresistance to the standard-of-care drug, paclitaxel. To further understand the mechanism by which NF1 exerts its effect on the response to chemotherapy, we analyzed public transcriptomic datasets. We found that NF1 expression inversely correlates with oxidative phosphorylation (OXPHOS) pathways. HGSC commonly metastasizes to adipose-rich tissues, suggesting that enhanced OXPHOS may be due to the utilization of fatty acids for energy through beta-oxidation (FAO). FAO is a preferred metabolic phenotype due to the prevalence of adipocytes in the omental microenvironment. Omental adipocytes foster survival of ovarian cancer cells under chemotherapy. Therefore, we hypothesize that NF1 loss amplifies adipocyte-mediated metabolic support to cancer cells following chemotherapy-induced stress. We are currently using direct and indirect coculture methods to demonstrate how NF1 loss promotes adipocyte-mediated resistance mechanisms in ovarian cancer. In summary, our findings suggest that loss of NF1 in high-grade serous ovarian carcinoma promotes chemoresistance, potentially through metabolic reprogramming involving enhanced oxidative phosphorylation and fatty acid oxidation fostered by adipocyte interactions in the tumor microenvironment (TME). Ongoing studies aim to elucidate the mechanism of this crosstalk, with the goal of identifying novel therapeutic vulnerabilities in NF1-deficient tumors. Citation Format: Olivia El Naggar, Binh Ha, Pedro Urquiza, Cristina Martel, Haley Decker, Brett Baskovich, Gabriele Romano. NF1 loss of function enhances chemoresistance in high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A007.