Combination therapy with AKT and MEK inhibitors is effective in patient-derived models of adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy with frequent metastases and poor survival due to chemoresistance and the lack of targetable oncogenic drivers. ~80% of ACC tumors overexpress IGF2, yet targeting the IGF2-IGFR1 axis in ACC has not been successful in the clinic. Here, we hypothesized that targeting additional survival pathways in combination with IGFR1 inhibition would be more effective in ACC than IGFR1 inhibition alone. Using a high-throughput screening platform (n=2803 compounds), we identified inhibitors of the MAPK pathway, to be highly synergistic with IGFR1 inhibition. MEK inhibitors were chosen for further evaluation given the safety, tolerability, and broad clinical activity. IGFR1 and MEK inhibitors were strongly synergistic in cytotoxicity across ACC cell lines (n=2) and short-term ACC organoids (PDOs) (n=8) derived from surgical tissue resections. Genetic depletion of IGF2 significantly inhibited growth with MEK inhibition and genetic depletion of MEK1 inhibited growth with IGFR1 inhibition in ACC cell lines. We then sought to identify signaling pathways downstream of IGFR1 that may be more amenable to clinical translation as IGF1R inhibitors are not FDA approved in cancer. Surprisingly, we found that linsitinib completely downregulated phospho-AKT suggesting AKT is a key downstream pathway of IGF2-IGFR1 in ACC. Accordingly, we observed strong synergy in cytotoxicity with combined AKT and MEK inhibition among ACC cell lines and short-term ACC PDOs. In vivo, the 2-drug AKT and MEK inhibitor combination demonstrated greater anti-tumor activity than either agent alone in an ACC cell-line xenograft and two chemoresistant ACC patient-derived xenograft models. Our results demonstrate a novel, active drug combination in refractory ACC that warrants clinical investigation.