Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status

Bittner, Madison; Llaurado Fernandez, Marta; Hoenisch, Joshua; Leung, Yuen Yee; Kim, Hannah; Wong, Nelson K. Y.; Pishas, Kathleen I.; Cheasley, Dane; Cowley, Karla J.; Simpson, Kaylene J.; Lin, Yen-Yi; Volik, Stanislav; Le Bihan, Stephane; Collins, Colin C.; Köbel, Martin; Carey, Mark S.

doi:10.3390/ijms27041774

Open AccessArticle

Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status

by

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,*

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

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(4), 1774; https://doi.org/10.3390/ijms27041774

Submission received: 13 December 2025 / Revised: 29 January 2026 / Accepted: 5 February 2026 / Published: 12 February 2026

(This article belongs to the Section Molecular Oncology)

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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

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MDPI and ACS Style

Bittner, M.; Llaurado Fernandez, M.; Hoenisch, J.; Leung, Y.Y.; Kim, H.; Wong, N.K.Y.; Pishas, K.I.; Cheasley, D.; Cowley, K.J.; Simpson, K.J.; et al. Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status. Int. J. Mol. Sci. 2026, 27, 1774. https://doi.org/10.3390/ijms27041774

AMA Style

Bittner M, Llaurado Fernandez M, Hoenisch J, Leung YY, Kim H, Wong NKY, Pishas KI, Cheasley D, Cowley KJ, Simpson KJ, et al. Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status. International Journal of Molecular Sciences. 2026; 27(4):1774. https://doi.org/10.3390/ijms27041774

Chicago/Turabian Style

Bittner, Madison, Marta Llaurado Fernandez, Joshua Hoenisch, Yuen Yee Leung, Hannah Kim, Nelson K. Y. Wong, Kathleen I. Pishas, Dane Cheasley, Karla J. Cowley, Kaylene J. Simpson, and et al. 2026. "Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status" International Journal of Molecular Sciences 27, no. 4: 1774. https://doi.org/10.3390/ijms27041774

APA Style

Bittner, M., Llaurado Fernandez, M., Hoenisch, J., Leung, Y. Y., Kim, H., Wong, N. K. Y., Pishas, K. I., Cheasley, D., Cowley, K. J., Simpson, K. J., Lin, Y.-Y., Volik, S., Le Bihan, S., Collins, C. C., Köbel, M., & Carey, M. S. (2026). Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status. International Journal of Molecular Sciences, 27(4), 1774. https://doi.org/10.3390/ijms27041774

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Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status

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