Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma - Abstract

Sep 23, 2026

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Low-grade serous ovarian carcinoma (LGSOC) often presents at advanced stages with high mortality, motivating improved therapeutic efficacy and predictive biomarkers for MAPK- and cell-cycle–targeted approaches. The study assessed p16/CDKN2A-related cell-cycle protein expression by immunohistochemistry across 186 LGSOC cases, and tested MEK inhibition with trametinib combined with CDK4/6 inhibition using palbociclib in preclinical models. Abnormal p16 expression correlated with worse survival and defined mechanistic determinants of treatment sensitivity, including KRAS/NF1 mutations, low pRb levels, synergistic antiproliferation in specific genetic contexts, and cyclin D1/E1–associated acquired resistance.

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Abstract

Introduction

Article Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status Madison Bittner 1,†, Marta Llaurado Fernandez 1,†, Joshua Hoenisch 1, Yuen Yee Leung 1, Hannah Kim 1, Nelson K. Y. Wong 2, Kathleen I. Pishas 3,4, Dane Cheasley 3,4, Karla J. Cowley 5, Kaylene J. Simpson 5, Yen-Yi Lin 6,7, Stanislav Volik 6, Stephane Le Bihan 6, Colin C. Collins 6,7, Martin Köbel 8 and Mark S. Carey 1,9, * Academic Editor: Stergios Boussios Received: 13 December 2025 Revised: 29 January 2026 Accepted: 5 February 2026 Published: 12 February 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC V6H 3N1, Canada 2 Department of Experimental Therapeutics, BC Cancer, Vancouver, BC V5Z 1L3, Canada 3 Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia 4 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia 5 Victorian Centre for Functional Genomics, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia 6 Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada 7 Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada 8 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada 9 Department of Clinical Research, BC Cancer, Vancouver, BC V5Z 1L3, Canada * Correspondence: mark.carey@vch.ca or mark.carey@vgh.ca † These authors contributed equally to this work. Abstract Low-grade serous ovarian carcinoma (LGSOC) usually presents in advanced stages and is associated with a high mortality rate. Clinical trials targeting the MAPK and cell cycle pathways in LGSOC have shown promising results for its treatment, however there is a need to improve efficacy and define predictive biomarkers to guide patient selection for treatment using these agents. We therefore evaluated cell cycle protein expression by immunohistochemistry (IHC) in 186 LGSOC cases, and evaluated the efficacy of the MEK inhibitor, trametinib, in combination with the CDK4/6 inhibitor, palbociclib, in preclinical models of LGSOC. Abnormal p16 expression was observed in 20% of primary and 46% of recurrent tumors, and it was associated with poorer survival (log-rank p = 0.005) . Notably, cell lines with increased sensitivity to trametinib were more likely to harbor mutations in KRAS or NF1 and displayed low pRb levels. Palbociclib showed limited efficacy in vitro; however, the combination of palbociclib and trametinib treatment produced synergistic antiproliferative effects in KRAS/NF1-wild-type cell lines, which displayed higher pRb levels. Acquired drug resistance was linked to increased cyclin D1/E1 expression. This study confirms abnormal p16 IHC as a negative prognostic marker in LGSOC and establishes key determinants of sensitivity to CDK4/6 inhibitor-based therapy. Keywords: ovarian cancer; low-grade serous ovarian carcinoma; MAPK; p16/CDKN2A; targeted therapies; palbociclib; trametinib 1. Introduction Low-grade serous ovarian carcinoma (LGSOC) is recognized as a distinct entity for its unique clinical, pathological, and molecular features [1] . As a rare cancer it accounts for only 2–5% of all ovarian carcinomas and approximately 1500 cases are diagnosed annually in Canada and the United States [1,2] . Compared with high-grade serous ovarian cancer (HGSOC), LGSOC occurs in younger women (median age 45–55 vs. 63 years) and exhibits relative chemoresistance [2–5]. Standard treatment usually consists of cytoreductive surgery then platinum-based chemotherapy followed by hormonal maintenance therapy [5,6] . As most LGSOC present in advanced stages (stage III–IV), and current therap

FAQs

What biomarker was evaluated for prognosis in low-grade serous ovarian carcinoma?

The study evaluated cell-cycle protein expression with immunohistochemistry, focusing on abnormal p16 expression (p16/CDKN2A). Abnormal p16 was associated with poorer survival.

How were trametinib and palbociclib tested in the research?

Trametinib (a MEK inhibitor) was evaluated in combination with palbociclib (a CDK4/6 inhibitor) using preclinical models of LGSOC, including in vitro cell line studies.

Which genetic features were linked to higher sensitivity to trametinib-based treatment?

Cell lines with increased sensitivity to trametinib were more likely to carry KRAS or NF1 mutations and to show low pRb levels, while synergy with palbociclib occurred in KRAS/NF1 wild-type lines with higher pRb levels.

Sep 23, 2026

Uploaded by Theodore