Integrated mutational landscape analysis of uterine leiomyosarcomas

Significance Identification of novel, effective treatment modalities for patients with uterine leiomyosarcomas (uLMS) remains an unmet medical need. Using an integrated whole-genome, whole-exome, and RNA-Seq analysis, we identified recurrently mutated genes and deranged pathways, including the homologous-recombination repair (HRR) pathway deficiency (HRD), alternative lengthening of telomere (ALT), C-MYC/BET, and PI3K-AKT-mTOR pathways as potential targets. Using two fully sequenced patient-derived xenografts (PDXs) harboring deranged C-MYC/BET and PTEN/PIK3CA pathways and/or an HRD signature (i.e., LEY11 and LEY16), we found olaparib (PARPi), GS-626510 (BETi), and copanlisib (PIK3CAi) monotherapy to significantly inhibit in vivo uLMS PDXs growth. Our integrated genetic analysis, combined with in vivo preclinical validation experiments, suggests that a large subset of uLMS may potentially benefit from existing PARPi/BETi/PIK3CAi-targeted drugs.