Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma
摘要
Osteosarcoma (OS) is a primary malignant bone tumor primarily affecting children and adolescents. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of 41 specimens revealed MCL1 amplification in 46.3% of patients with OS. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells, and the pharmacological efficacy of Mcl-1 inhibitors was correlated with MCL1 copy numbers. Chromosome 1q21.2-3 region, where MCL1 is located, contains multiple genes related to the IGF-1R/PI3K pathway, including PIP5K1A, TARS2, OUTD7B, and ENSA, which also showed increased copy numbers in MCL1-amplified OS cells. Furthermore, combining Mcl-1 inhibitors with IGF-1R inhibitors resulted in synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling and suppressed tumor growth in MCL1-amplified OS xenograft models. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, which occurred in approximately half of OS patients, may serve as a predictive biomarker for the combination therapy with an Mcl-1 inhibitor and an IGF1R inhibitor.