PRJNA498216
A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma
Guenther LM, Dharia NV, Ross L, Conway AS, Robichaud AL, Catlett JL, Wechsler C, Frank ES, Goodale AB, Church AJ, Tseng Y-Y, Guha R, McKnight CG, Janeway KA, Boehm JS, Mora J, Davis MI, Alexe G, Piccioni F, Stegmaier K.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 bone tumor. Given the heightened efficacy of this class in combination with targeted drugs 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 and biologically relevant combinations for use with CDK4/6 inhibitors in Ewing. We performed a genome-scale open-reading frame (ORF) rescue screen in two Ewing cell lines sensitive to CDK4/6 inhibitors to identify genes conferring resistance. This screen revealed IGF1R as a gene whose overexpression promoted drug escape. In parallel, we established resistance to CDK4/6 inhibitors in a Ewing cell line and found elevated levels of phospho-IGF1R, supporting the relevance of IGF1R signaling to acquired resistance. Additionally, in a small molecule screen in Ewing cells, an IGF1R inhibitor scored as synergistic with CDK4/6 inhibitor treatment. The drug combination was synergistic in cell lines in vitro and was active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6 inhibition in Ewing sarcoma and that dual targeting of CDK4/6 and IGF1R provides a candidate synergistic combination for clinical application in this disease.