Journal article
Co-targeting the PI3K-Akt pathway improves response to MEK inhibition in low-grade serous ovarian cancer cell lines
Gynecologic oncology, Vol.204, pp.194-201
12/05/2025
DOI: 10.1016/j.ygyno.2025.11.016
PMID: 41351945
Abstract
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, however, nearly all patients eventually develop therapeutic resistance and progressive disease, which confers a dismal prognosis. Here, we aim to characterize biological responses of LGSOC to MEK inhibition at the molecular level.
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.
CRISPR kinome screens identified several protein kinases, particularly within the PI3K-Akt pathway, whose loss correlated with outgrowth of trametinib-resistant LGSOC cell populations, indicative of synthetic lethal interaction. Western blotting confirmed upregulation of Akt signaling upon MEK inhibition in a panel of LGSOC cell lines, and preventing this upregulation by co-inhibiting AKT with capivasertib produced synergistic antiproliferative effects in vitro.
LGSOC responds to MEK inhibition by upregulating PI3K-Akt signaling, thereby promoting cell survival and proliferation. Our research identified significant upregulation of the PI3K-Akt pathway in response to MEK inhibition. While targeted inhibition of AKT had minimal impact alone, combination with MEK inhibitors produced strong synergistic suppression of proliferation in LGSOC cells. This combination strategy could potentially be used to prevent or reverse the emergence of MEK inhibitor resistance in LGSOC patients.
Details
- Title: Subtitle
- Co-targeting the PI3K-Akt pathway improves response to MEK inhibition in low-grade serous ovarian cancer cell lines
- Creators
- Rebekah M Peplinski - University of IowaJesse D Riordan - University of IowaJacob L Schillo - University of IowaElizabeth C Hannan - University of IowaSilvana Pedra Nobre - University of Iowa, Anatomy & Cell Biology, 375 Newton Road, 3210 MERF, Iowa City, Iowa 52242, United StatesYasmin A Lyons - University of IowaKeely K Ulmer - University of IowaMichael J Goodheart - University of IowaAdam J Dupuy - University of Iowa, Anatomy & Cell Biology, 375 Newton Road, 3210 MERF, Iowa City, Iowa 52242, United States. Electronic address: adam-dupuy@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Gynecologic oncology, Vol.204, pp.194-201
- DOI
- 10.1016/j.ygyno.2025.11.016
- PMID
- 41351945
- NLM abbreviation
- Gynecol Oncol
- ISSN
- 0090-8258
- eISSN
- 1095-6859
- Publisher
- Elsevier
- Language
- English
- Date published
- 12/05/2025
- Academic Unit
- Anatomy and Cell Biology; Pathology; Obstetrics and Gynecology
- Record Identifier
- 9985090627502771
Metrics
13 Record Views