Combination Therapy with AKT and MEK Inhibitors is Effective in Patient-Derived Models of Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare, aggressive, chemoresistant malignancy with limited effective systemic therapies and few recurrent actionable oncogenic drivers. Although IGF-2 is overexpressed in approximately 80% of ACCs, clinical inhibition of the IGF-1R/InsR axis has not improved outcomes. To identify clinically tractable combination strategies that enhance IGF-1R/InsR inhibition in ACC, we performed a quantitative high-throughput combinatorial screen of 2,803 mechanistically annotated oncology compounds with the IGF 1R/InsR inhibitor linsitinib in an ACC cell line. Downstream effects of IGF-1R/InsR signaling were assessed to identify actionable nodes for combination targeting. Candidate combinations were validated using short-term ACC patient-derived organoids (PDOs) and patient-derived xenograft (PDX) models. The screen identified MAPK pathway inhibitors-particularly MEK inhibition-as the top synergistic partners with IGF-1R/InsR inhibition. Genetic or pharmacologic inhibition of IGF-1R/InsR and MEK signaling suppressed ACC growth in vitro. Downstream profiling of IGF-1R/InsR signaling identified AKT as a major effector, supporting direct AKT targeting as a translatable substitute for IGF-1R/InsR inhibition in ACC. Accordingly, the AKT inhibitor capivasertib synergized with the MEK inhibitor cobimetinib in ACC cell lines and six ACC PDO models. In vivo, combined AKT and MEK inhibition reduced tumor growth more than either agent alone in an ACC xenograft and two ACC chemotherapy-resistant PDX models with acceptable tolerability. These data identify AKT as a critical survival pathway in ACC and support combined AKT and MEK inhibition with FDA-approved agents as a therapeutic approach for chemotherapy-resistant ACC.

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Journal
Cancer Research Communications
Published
2026-11-05
DOI
https://doi.org/10.1158/2767-9764.crc-26-0581
Primary Topic
Adrenal and Paraganglionic Tumors
Type
article
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Combination Therapy with AKT and MEK Inhibitors is Effective in Patient-Derived Models of Adrenocortical Carcinoma

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Cancer Research Communications
Adrenal and Paraganglionic Tumors
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Combination Therapy with AKT and MEK Inhibitors is Effective in Patient-Derived Models of Adrenocortical Carcinoma

Briana Noel Cortez, Savannah Wood, Stephen M. Hewitt, Nitin Roper, Afeez Adekunle Ishola, Craig J. Thomas, Yoo Sun Kim, Xiaohu Zhang, Jaydira Del Rivero, Suresh Kumar, Jonathan Matthew Hernandez, Katja Kiseljak‐Vassiliades, Yasuhiro Arakawa, David O. Holland, Xiaoling Luo, Yves G. Pommier, Ross G. Lake, Mirit I. Aladjem, Nai-Yun Sun, Crystal G. McKnight, Anthony Garrison, Diana Grace Varghese, Arnulfo Mendoza, Margaret E. Wierman, Chuong D. Hoang, Liang Liu, George I Karadimov
article en

Abstract

Adrenocortical carcinoma (ACC) is a rare, aggressive, chemoresistant malignancy with limited effective systemic therapies and few recurrent actionable oncogenic drivers. Although IGF-2 is overexpressed in approximately 80% of ACCs, clinical inhibition of the IGF-1R/InsR axis has not improved outcomes. To identify clinically tractable combination strategies that enhance IGF-1R/InsR inhibition in ACC, we performed a quantitative high-throughput combinatorial screen of 2,803 mechanistically annotated oncology compounds with the IGF 1R/InsR inhibitor linsitinib in an ACC cell line. Downstream effects of IGF-1R/InsR signaling were assessed to identify actionable nodes for combination targeting. Candidate combinations were validated using short-term ACC patient-derived organoids (PDOs) and patient-derived xenograft (PDX) models. The screen identified MAPK pathway inhibitors-particularly MEK inhibition-as the top synergistic partners with IGF-1R/InsR inhibition. Genetic or pharmacologic inhibition of IGF-1R/InsR and MEK signaling suppressed ACC growth in vitro. Downstream profiling of IGF-1R/InsR signaling identified AKT as a major effector, supporting direct AKT targeting as a translatable substitute for IGF-1R/InsR inhibition in ACC. Accordingly, the AKT inhibitor capivasertib synergized with the MEK inhibitor cobimetinib in ACC cell lines and six ACC PDO models. In vivo, combined AKT and MEK inhibition reduced tumor growth more than either agent alone in an ACC xenograft and two ACC chemotherapy-resistant PDX models with acceptable tolerability. These data identify AKT as a critical survival pathway in ACC and support combined AKT and MEK inhibition with FDA-approved agents as a therapeutic approach for chemotherapy-resistant ACC.

Cancer Research Communications
Jikei University School of Medicine (JP), National Institutes of Health (US), National Cancer Institute (MY), National Cancer Institute (US), National Center for Advancing Translational Sciences (US), National Institutes of Health Clinical Center (US), University of Colorado Anschutz Medical Campus (US)
Openalex Percentile: Top 11%
Adrenal and Paraganglionic Tumors
DOIOpen Access PDFOpenAlex
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