Abstract A038: Targeting RAS in gynecologic cancers

Abstract RAS and MAPK pathway alterations are frequent in many histologic subtypes of gynecologic cancers. Promising clinical efficacy has been reported with the combination of avutometinib (RAF-MEK clamp) and defactinib (FAK inhibitor) in KRAS-mutant low-grade serous ovarian cancer, and the combination of trametinib (MEK inhibitor) and ABT-263 (BCL-XL inhibitor) in gynecologic cancers (endometrial, ovarian, cervical). However, novel approaches to RAS inhibition have not yet been fully exploited in the treatment of gynecologic malignancies. The purpose of this study was to analyze RAS alterations in an institutional cohort of gynecologic cancers, and to establish patient-derived models of RAS-mutant rare gynecologic cancers in which to evaluate RAS targeted therapies. Targeted next-generation sequencing of an institutional cohort identified RAS gene alterations in all subtypes of gynecologic cancers. RAS mutations (KRAS, NRAS, or HRAS) were identified in approximately 4000 samples, including 11% of ovarian cancers (KRAS G12A, C, D, R, S, V, G13C, D, others; NRAS hotspots), 26% of uterine epithelial cancers (KRAS G12A, C, D, V, G13C, D, other; HRAS and NRAS hotspots), 10% of cervical cancers (KRAS G12C, D, V), 10% of vaginal cancers (KRAS G12A, V; NRAS hotspots), and 6% of vulvar cancers (HRAS). KRAS amplifications were present in about 3. 5% of ovarian cancers and 1% of endometrial cancers. Mucinous ovarian cancers demonstrated the highest frequency of KRAS alterations, occurring in at least 67% of cases. We prospectively collected fresh tissue samples from surgical resections of rare gynecologic cancers and attempted patient-derived organoid (PDO) and/or patient-derived xenograft (PDX) generation from selected cases. As proof of concept, we successfully established a PDO and a PDX model from a KRAS G12D mutated mucinous ovarian cancer, which were sustained for multiple passages in vitro or in vivo. The PDO cells resembled the original patient tumor morphologically and harbored the same mutational profile including KRAS G12D, as confirmed by next-generation sequencing. PDO cells were propagated for multiple passages with maintenance of the KRAS G12D mutation as assessed by digital droplet PCR. Response of the KRAS G12D PDO model to a panel of KRAS targeted agents was assessed using a microfluidic device and fluorescent staining for live, dead, and apoptotic cells. Six-day treatment with MRTX1133 (KRAS G12D inhibitor), AMG 410 (pan-KRAS inhibitor), RMC-6236 (daraxonrasib, RAS (ON) inhibitor), or RMC-9805 (zoldonrasib, RAS (ON) G12D selective inhibitor), each at 100nM, resulted in 70-95% growth inhibition. In conclusion, leveraging the substantial frequency of RAS alterations in rare gynecologic cancers, we have established PDO and PDX models of a KRAS G12D mutated ovarian cancer and demonstrated ex vivo sensitivity to a panel of KRAS inhibitors with different mechanisms of action. Targeting RAS may be a promising treatment approach in gynecologic cancers. Citation Format: Elizabeth H. Stover, Magdalena Zielinska, Minh Ha, Satyakam Mishra, David L. Kolin, Cam Anh Tran, Cloud P. Paweletz, Andrew J. Aguirre, Guruprasad Ananda, Elena Ivanova, Ursula A. Matulonis, Joyce F. Liu. Targeting RAS in gynecologic cancers abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A038.