Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Osteosarcoma (OS) is a primary bone cancer affecting children and adolescents.
• Limited progress in OS drug development stems from a lack of identified common oncogenic drivers.
• Identifying actionable targets is crucial for advancing OS therapy.

Purpose of the Study:

• To investigate the role of MCL1 gene copy number alterations in osteosarcoma.
• To evaluate the therapeutic potential of Mcl-1 inhibitors in MCL1-amplified OS.
• To explore combination therapies targeting MCL1 and IGF-1R pathways.

Main Methods:

• Fluorescence in situ hybridization (FISH) to detect MCL1 amplification in 41 OS specimens.
• Genetic and pharmacological inhibition of MCL1 in OS cells.
• Assessment of combination therapy with Mcl-1 and IGF-1R inhibitors in vitro and in OS xenograft models.

Main Results:

• MCL1 amplification was identified in 46.3% of OS patients.
• Genetic MCL1 inhibition induced significant apoptosis in amplified OS cells.
• Therapeutic efficacy of Mcl-1 inhibitors correlated with MCL1 copy number.
• Co-targeting MCL1 and IGF-1R synergistically induced cell death and suppressed tumor growth.
• Co-amplification of genes in the 1q21.2-3 region, including those in the IGF-1R/PI3K pathway, was observed.

Conclusions:

• Genomic amplification of MCL1 is a frequent event in osteosarcoma.
• MCL1 amplification serves as a predictive biomarker for Mcl-1 inhibitor therapy.
• Combination therapy with Mcl-1 and IGF-1R inhibitors demonstrates synergistic efficacy in MCL1-amplified OS.
• Targeting the MCL1/IGF-1R axis offers a promising therapeutic strategy for a significant subset of osteosarcoma patients.