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

Georgia Zoumpoulidou,Nischalan Pillay,Jiten Manji,Caterina Mancusi,Maxime Tarabichi,Camilla Cristalli,Katia Scotlandi,Carlos Alvarez-Mendoza,Errin Roy,Milly Denman,Sibylle Mittnacht,Ritika-Mahmuda Ahmed,Sandra J Strauss,Christopher D Steele,Lauren R Davies

doi:10.1038/s41467-021-27291-8

Georgia Zoumpoulidou, Nischalan Pillay + Show 13 more

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https://doi.org/10.1038/s41467-021-27291-8

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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.

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Loss-of-function mutations in the RB1-encoded protein (RB1) tumour suppressor are key drivers in cancer, including osteosarcoma
A strong association between olaparib sensitivity and RB1 status extended to a poly-cancer cell line panel, with median area-under-the-curve (AUC) values significantly lower in RB1defective compared to RB1-normal lines (Supplementary Fig. 1d–f), indicative that RB1 status in cancers is associated with, and may predict, hypersensitivity to PARPi
While consistent with an increased dependency on PARP1,2 catalysis, these results indicate that PARP trapping may be an important mechanistic determinant for single-agent potency in RB1-mutant osteosarcoma, as is known for BRCA1,2-mutated cancers[22]

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Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. We demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase[1,2] 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. Sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Biallelic mutations targeting RB1 are prominently associated with difficult to treat cancers, including osteosarcoma. 143b MHM CAL72 G292 MG63 OS25HAL HOS SJSA/OSA HOSMNNG U2OS (sanger) U2OS KPD CAPAN1 (BRCA- mut) HU09 NY OHSN SAOS2 (sanger) HU03N1 LM7 SAOS2

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