Abstract 2986: Genomic amplification of MCL1 as a therapeutic target for osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor that predominantly occurs in children, adolescents, and young adults. The treatment for OS that combines surgery with chemotherapy, which consists of a four-drug combination of doxorubicin (DOX), cisplatin (CDDP), high-dose methotrexate (MTX), and ifosfamide, was established in 1970s, and it is still used as a standard therapy. 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 increased vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of formalin-fixed paraffin-embedded specimens revealed MCL1 amplification in 46.3% of patients with OS at the JFCR hospital (N = 41). Furthermore, analysis of the TARGET OS dataset, which comprises pediatric patients with OS (N = 81), found that the frequency of MCL1 amplification was notably higher, at 70.4%. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells. Pharmacological inhibition of MCL1 demonstrated a negative correlation between MCL1 copy numbers and sensitivity to Mcl-1 inhibitors, including MIK665 and AZD5991, with a Pearson’s r value of -0.65 (p = 0.03) across OS cell lines. The 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. Additionally, the combination of MIK665 with IGF-1R inhibitors, including OSI906, AEW541, and AZD3463, induced synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling in OS cells. In a NOS-10 (which has 16 copies of MCL1) xenograft model, MIK665 significantly suppressed tumor growth, and its antitumor effect was remarkably enhanced by combining with OSI906. This trend was also observed in a NOS-1 (with 5 copies of MCL1) xenograft model, but the enhancement was more modest than in the NOS-10 model. Moreover, the combination therapy of AZD5991 with OSI906 also reduced tumor growth in the NOS-10 xenograft model. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, observed in nearly half of OS patients, may act as a predictive biomarker for combination therapy with an Mcl-1 inhibitor and an IGF1-R inhibitor. Citation Format: Satoshi Takagi, Tianyi Huang, Ryohei Katayama. Genomic amplification of MCL1 as a therapeutic target for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2986.