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

Georgia Zoumpoulidou, Carlos Alvarez-Mendoza, Caterina Mancusi, Ritika-Mahmuda Ahmed, Milly Denman, Christopher D. Steele, Maxime Tarabichi, Errin Roy, Lauren R. Davies, Jiten Manji, Camilla Cristalli, Katia Scotlandi, Nischalan Pillay, Sandra J. Strauss and Sibylle Mittnacht ()
Additional contact information
Georgia Zoumpoulidou: University College London
Carlos Alvarez-Mendoza: University College London
Caterina Mancusi: University College London
Ritika-Mahmuda Ahmed: University College London
Milly Denman: University College London
Christopher D. Steele: University College London
Maxime Tarabichi: The Francis Crick Institute
Errin Roy: University College London
Lauren R. Davies: University College London
Jiten Manji: University College London
Camilla Cristalli: IRCCS Istituto Ortopedico Rizzoli
Katia Scotlandi: IRCCS Istituto Ortopedico Rizzoli
Nischalan Pillay: University College London
Sandra J. Strauss: University College London
Sibylle Mittnacht: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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-defective cancer cells, including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-defective backgrounds and prolongs survival of mice carrying human RB1-defective osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that 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 personalised strategy for RB1-mutated osteosarcoma and other cancers.

Date: 2021
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DOI: 10.1038/s41467-021-27291-8

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