Takagi Satoshi, Nakajima Mikako, Koike Sumie, Takami Miho, Sugiura Yoshiya, Sakata Seiji, Baba Satoko, Takemoto Ai, Huang Tianyi, Seto Yosuke, Saito Masanori, Funauchi Yuki, Ae Keisuke, Takeuchi Kengo, Fujita Naoya, Katayama Ryohei
Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan.
Oncogene. 2025 Apr;44(12):794-804. doi: 10.1038/s41388-024-03251-6. Epub 2024 Dec 11.
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.
骨肉瘤（OS）是一种主要影响儿童和青少年的原发性恶性骨肿瘤。OS药物研发缺乏进展部分归因于OS中尚未明确的可作用致癌驱动因素。在本研究中，我们证明MCL1的拷贝数增加在OS中频繁发生，导致对基于Mcl-1抑制剂的疗法敏感。对41个标本进行荧光原位杂交分析显示，46.3%的OS患者存在MCL1扩增。对MCL1进行基因抑制可在MCL1扩增的OS细胞中诱导显著凋亡，且Mcl-1抑制剂的药理疗效与MCL1拷贝数相关。MCL1所在的1q21.2 - 3染色体区域包含多个与IGF-1R/PI3K通路相关的基因，包括PIP5K1A、TARS2、OUTD7B和ENSA，这些基因在MCL1扩增的OS细胞中也显示出拷贝数增加。此外，将Mcl-1抑制剂与IGF-1R抑制剂联合使用可通过克服IGF信号激活赋予的耐药性导致协同性细胞死亡，并在MCL1扩增的OS异种移植模型中抑制肿瘤生长。这些结果表明，在大约一半的OS患者中出现的1q21.2 - 3区域MCL1基因组扩增可能作为Mcl-1抑制剂和IGF1R抑制剂联合治疗的预测生物标志物。
