Therapeutic vulnerability to PARP1/2 inhibition in RB1-mutant osteosarcoma

Abstract

BackgroundLoss-of-function mutations of the retinoblastoma tumour suppressor RB1 are key drivers in cancer, with prominent involvement in the natural history of Osteosarcoma (OS). RB1 loss-of-function compromises genome maintenance in cells and hence could yield vulnerability to therapeutics targeting such processes. MethodWe assessed the response to Poly-ADP-Polymerase1/2 inhibitors (PARPi) in histiotype-matched cancer cell lines differing in RB1 status including an extended panel of OS lines, measuring viability, clonogenic activity and inhibition of xenograft growth in vivo. We used mutational signature analysis and RAD51 immunostaining to assess competence for homologous repair defect (HRd). ResultsWe report selective hypersensitivity to clinically-approved PARPi in OS lines with RB1 mutation, which extends to other cancer histiotypes and is induced in RB1-normal OS following engineered RB1 loss. PARPi treatment caused extensive cell death in RB1-mutated OS and extended survival of mice carrying human RB1-mutated OS grafts. Sensitivity in OS with natural or engineered RB1 loss surpassed that seen in BRCA-mutated backgrounds where PARPi are showing clinical benefit. PARPi sensitivity was not associated with loss of RAD51 recruitment and HRd-linked mutational signatures, which predict PARPi sensitivity in cancers with BRCA1/2 loss, but linked to rapid activation of replication checkpoint signalling with S phase transit critical for the death response observed. ConclusionOur work demonstrates that mutations in RB1 causes clinically relevant hypersensitivity to approved PARP1/2-targeting therapeutics and advocates PARP1/2 inhibition as a novel, genome lead strategy for RB1-mutated osteosarcoma.