Integrated genomic approaches to characterize molecular responses to targeted therapies in low-grade serous ovarian cancer

Low-grade serous ovarian cancer (LGSOC) is a unique subtype with distinct molecular and clinical characteristics. While this subtype is relatively rare (~5%) and has a low mortality rate, patients are typically younger at diagnosis and experience few (if any) disease-free intervals. Current standard chemotherapy is ineffective for LGSOC (<10% response rate), however, the presence of frequent genetic alterations in the mitogen-activated protein kinase (MAPK) pathway have led to targeted therapeutic clinical trials. Recent clinical trials utilizing inhibitors of mitogen-activated protein kinase kinase (MEK) (a key mediator of MAPK signaling), particularly trametinib or avutometinib/defactinib combination, have shown efficacy in patients with recurrent LGSOC. Unfortunately, after initial response, patients develop progressive disease, with no remaining treatment options. Here, we sought to characterize biological responses of LGSOC to MEK inhibition at the molecular level, and identify adaptive mechanisms of drug resistance, thereby establishing candidates for further exploration as therapeutic targets to prevent or reverse LGSOC progression.