Abstract 3581: IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma

Abstract

Abstract Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with limited treatment options and poor prognosis. IGF2, the ligand for IGFR1, is highly expressed in ACC. However, linsitinib, an IGFR1 inhibitor, failed to improve overall survival over placebo in a randomized, phase 3 clinical trial of metastatic ACC. We hypothesized that combination therapy with IGFR1 inhibition may have greater anti-tumor efficacy in ACC than IGFR1 inhibition alone. To test this hypothesis, we performed high-throughput cell toxicity screening of 2803 clinical-stage compounds with linsitinib in an ACC cell line. MAPK inhibitors were among the top screening hits. MEK inhibitors were chosen for further evaluation given the safety, tolerability, and broad clinical activity of these FDA-approved agents. IGFR1 and MEK inhibitors were strongly synergistic in cytotoxicity across ACC cell lines, ACC organoid short-term cultures derived from surgical tissue resections (PDOs), and PDX-derived organoids (PDXOs). Genetic depletion of IGF2 significantly inhibited growth with cobimetinib and genetic depletion of MEK1 inhibited growth with linsitinib in ACC cell lines. Combination IGFR1 and MEK inhibition downregulated ERK phosphorylation and increased apoptosis compared to either IGFR1 or MEK inhibition alone. Linsitinib combined with cobimetinib significantly reduced tumor growth compared to either linsitinib or cobimetinib alone in an ACC xenograft model. Our study provides preclinical support for testing the combination of IGFR1 and MEK inhibition in patients with ACC. Citation Format: Suresh Kumar, Nai-Yun Sun, Yasuhiro Arakawa, Diana Varghese, Chuong D. Hoang, Jonathan M. Hernandez, Yves Pommier, Craig Thomas, Jaydira Del Rivero, Nitin Roper. IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3581.