Abstract
Integrated genomic approaches to characterize biologic responses to MEK inhibition and mechanisms of therapeutic resistance in low-grade serous ovarian cancer
Gynecologic oncology, Vol.200(Supplement 1), pp.207-208
09/2025
DOI: 10.1016/j.ygyno.2025.04.269
Abstract
Objectives
Low-grade serous ovarian cancer (LGSOC) frequently harbors genetic alterations that activate the MAPK pathway, providing an oncogenic target for therapeutic intervention. Recent clinical trials utilizing inhibitors of MEK (a key mediator of MAPK signaling), particularly trametinib or avutometinib/defactinib combination, have shown efficacy in patients with recurrent LGSOC. Unfortunately, nearly all patients eventually develop therapeutic resistance and progressive disease, which confers a dismal prognosis. This study aimed to characterize biologic 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.
Methods
We performed a kinome-focused CRISPR knockout screen in LGSOC cell lines to identify synthetic lethal interactions between trametinib treatment and loss of specific protein kinases. Candidates were evaluated using western blotting and cell viability assays. We are currently conducting an unbiased forward genetic mutagenesis screen in vivo using a xenograft LGSOC mouse model to identify mechanisms of resistance to avutometinib/defactinib treatment. Disease progression is monitored via bioluminescence imaging. Once resistance develops, profiles of transposon-induced mutations will be generated for each tumor. Analysis of the full cohort will identify recurrently mutated genes in progressive tumors, which represent candidate drivers of avutometinib/defactinib resistance.
Results
CRISPR kinome screens identified several protein kinases, particularly within the PI3K/AKT pathway, whose loss correlated with the outgrowth of trametinib-resistant LGSOC cell populations, indicative of synthetic lethal interaction. Western blotting confirmed the upregulation of AKT signaling upon MEK inhibition in a panel of LGSOC cell lines. Preventing this upregulation by coinhibiting AKT with capivasertib produced synergistic antiproliferative effects in vitro. Ongoing efforts are focused on profiling tumors that progress through avutometinib/defactinib treatment in vivo in our xenograft screen to identify genes that are recurrently mutated in these drug-resistant samples, suggesting positive selection for their mutation during progression. Candidate resistance/progression drivers will be validated in vivo for oncogenic effects and molecular mechanisms of therapeutic resistance will be further characterized.
Conclusions
LGSOC responds to MEK inhibition by upregulating PI3K/AKT signaling, thereby promoting cell survival and proliferation. Targeting the MAPK and PI3K/AKT pathways concurrently could be an effective treatment for patients with LGSOC to prevent or reverse progression. Our avutometinib/defactinib resistance screen in an intraperitoneal xenograft model system may identify additional therapeutic targets to reduce the burden of this disease.
Details
- Title: Subtitle
- Integrated genomic approaches to characterize biologic responses to MEK inhibition and mechanisms of therapeutic resistance in low-grade serous ovarian cancer
- Creators
- Rebekah Peplinski - University of IowaJesse Riordan - University of IowaJacob Schillo - University of IowaSilvana Pedra NobreYasmin Lyons - University of IowaKeely Ulmer - University of IowaMichael Goodheart - University of IowaAdam Dupuy - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Gynecologic oncology, Vol.200(Supplement 1), pp.207-208
- DOI
- 10.1016/j.ygyno.2025.04.269
- ISSN
- 0090-8258
- eISSN
- 1095-6859
- Publisher
- Elsevier
- Language
- English
- Date published
- 09/2025
- Academic Unit
- Anatomy and Cell Biology; Pathology; Obstetrics and Gynecology
- Record Identifier
- 9984969239602771
Metrics
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