A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma

Introduction: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma, an aggressive pediatric malignancy. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors (CDK4/6i) and biologically relevant combinations for use with CDK4/6i in Ewing. Experimental Design: We performed a genome-scale open-reading frame (ORF) screen in two Ewing cell lines sensitive to CDK4/6i to identify genes conferring resistance. Concurrently, we established resistance to CDK4/6i in a Ewing cell line. Results: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6i treatment. The combination of CDK4/6i and IGF1Ri were synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. Conclusions: Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6i in Ewing sarcoma and that dual targeting of CDK4/6 and IGF1R provides a candidate synergistic combination for clinical application in this disease.

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