The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma
Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation foradolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT hasbeen reported in other cancers, with no counterstrategies available. Using preclinical mousexenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset oftumors develop resistance that is associated with transcriptomic changes that occur in theabsence of recurrent genomic mutation. Importantly, a majority of resistant RMS modelsupregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factorphosphorylation and subsequent transcriptional expression of multidrug resistance ABCtransport proteins that rapidly efflux drugs from cells. We found that the PIK3CA inhibitoralpelisib re-sensitized resistant tumor cells to OT therapy by suppressing the expression of ABCtransport proteins. Excitingly, RMS use the same PIK3CA/AKT pathway activation to driveresistance to standard-of-care combination therapy vincristine, actinomycin D, andcyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistantRMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mousemodels resulting in reduced tumor burden and extended disease-free survival. Our work definesa common resistance pathway in RMS and has credentialled a new preclinical strategy to killtherapy resistant RMS. Overall design: Single cells were dissociated by tumor dissociation kit from PDX tumor on NSG mice and analyzed using scRNAseq.