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Abstract Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for adolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT has been reported in other cancers, with no counterstrategies available. Using preclinical mouse xenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset of tumors develop resistance that is associated with transcriptomic changes that occur in the absence of recurrent genomic mutation. Importantly, a vast majority of resistant RMS models upregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factor phosphorylation and subsequent transcriptional expression of multidrug resistance ABC transport proteins that rapidly efflux drugs from cells. Using dynamic real-time imaging of tumor growth and assessing drug responses at single-cell resolution in human cell line models, we found that the PIK3CA inhibitor alpelisib re-sensitized resistant RMS cells to OT therapy by suppressing the expression of ABC transport proteins. Excitingly, RMS uses the same PIK3CA/AKT pathway activation to drive resistance to standard-of-care combination therapy vincristine, actinomycin D, and cyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistant RMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mouse models resulting in reduced tumor burden and extended disease-free survival. Our work defines a common resistance pathway in RMS and has credentialled a new preclinical strategy to kill therapy-resistant RMS. Citation Format: Yueyang Wang, Qiqi Yang, Chuan Yan, David M. Langenau. The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A072.
Wang et al. (Thu,) studied this question.