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A pan-cancer study to identify and characterize synthetic lethal drugs in BAP1-deficient cancers

ABSTRACT: BRCA-1 Associated Protein (BAP1) is a deubiquitinating enzyme that acts as a tumour suppressor. Inactivating mutations in the BAP1 gene have been identified in many cancers including cholangiocarcinoma, hepatocellular carcinoma, mesothelioma, uveal melanoma and renal cell carcinoma. Current standard therapeutic approaches for BAP1-deficient tumours are not particularly promising, contributing to poor overall survival and disease-free survival rates. Here, we found BAP1 to mediate the turnover of the key proteins in the DNA nucleotide excision repair (NER) pathway, and therefore promotes DNA repair. Importantly, we demonstrate that the loss of functional BAP1 sensitise tumour cells to LSD1 inhibitor, SP2509, in vitro and in vivo, through further impairment of NER efficiency. When used in combination with PARP1 inhibitor, Olaparib, we show that a synergistic drug combination response is achieved. Overall, our study identifies a drug combination approach that has the potential to be exploited clinically to target BAP1 deficient tumours.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Radoslaw Mikolaj Sobota

PROVIDER: PXD028470 | JPOST Repository | Thu Sep 15 00:00:00 BST 2022

REPOSITORIES: jPOST

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			Action	DRS
	20190821_JH_EV_Ubi_TR1.raw	Raw
	20190821_JH_MUT_Ubi_TR1.raw	Raw
	20190821_JH_WT_Ubi_TR1.raw	Raw
	20190902_JH_EV_Ubi_TR2.raw	Raw
	20190902_JH_EV_Ubi_TR3.raw	Raw

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