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

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.