Proceedings of the National Academy of Sciences · 2021 · 118 citations · 55 references
MedicineGeneticsOncologyCancer GeneticsGenomicsMolecular OncologyCancer GenomicsDna SequencingMolecular Tumor ProfilingNext-generation SequencingNext-generation Sequencing In OncologyUterine LeiomyomaCopy Number GainsCopy Number LossesExome SequencingMen1 Gene AlterationsMen1 Gene MutationsSomatic Copy Number AlterationsSomatic MutationsTumor Mutation Analysis
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.
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