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

Abstract

Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-mutated cancer cells including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-mutated backgrounds and prolongs survival of mice carrying human RB1-mutated osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures, which predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a novel, personalised strategy for RB1-mutated osteosarcoma and other cancers.

Genome maintenance in retinoblastoma: Implications for therapeutic vulnerabilities (Review)

“…Notably, the DNA-repair hub has been found to be overlapping for survival of both RB1-inactivated tumors and MYCN-amplified tumors harboring intact RB1 gene (46), which implies a wide-range applicability of the chemosensitization strategies toward different RB subtypes. In line with this notion, poly (ADP-ribose) polymerase (PARP) inhibition was revealed to be efficacious for proliferation inhibition of RB1-mutated osteosarcoma cells, and the hypersensitivity to PARP inhibitors was associated with rapid activation of DNA replication checkpoint signaling, while no apparent defects in HR repair were observed in the RB1-mutated cells (98). These findings collectively suggest that the therapeutic vulnerabilities identified to be associated with RB1 loss hinge on DNA damage response and repair, albeit with variability in the detailed mechanisms of action.…”