Rat sarcoma inhibitors in and beyond gynecologic malignancies

Recent advances in direct rat sarcoma (RAS) inhibition and downstream pathway targeting have created novel therapeutic strategies which can be utilized in gynecologic oncology. This review examines RAS biology, lessons learned from other malignancies, and emerging strategies for gynecological malignancies.

KRAS G12C inhibitors in lung cancer established the clinical feasibility of direct RAS targeting, while colorectal cancer studies demonstrated the importance of lineage-specific combinations. KRAS G12D inhibitors, targeted protein degraders, and multiselective RAS(ON) inhibitors represent the next frontier in RAS inhibition, expanding therapeutic options across both gynecologic and nongynecologic tumors. In recurrent low-grade serous ovarian cancer, therapeutic advances have centered on inhibiting the downstream RAS-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase signaling pathway using MEK or combined RAF/MEK and focal adhesion kinase inhibitors, rather than direct RAS inhibition, demonstrating encouraging clinical responses, leading to accelerated approval for KRAS-mutant disease.

RAS-pathway directed therapy requires consideration of tumor lineage, specific alleles, and functional pathway dependence. Although clinical progress in gynecologic oncology is most relevant in low-grade serous ovarian cancer, emerging non-G12C therapies warrant further evaluation across gynecologic malignancies. Novel combinations and integrated biomarkers will be necessary to improve patient selection and overcome therapeutic resistance.