Identification of novel targeted therapies for BAP1 mutated tumors

Abstract

Purpose : The BRCA1 associated protein-1 (BAP1) is mutated in the majority of aggressive uveal melanomas (UMs). Somatic mutations in BAP1 have been also observed in other cancers making it a potential important target for therapy. The goal of this study was to identify potential novel targeted therapy for BAP1 mutated tumors.

Methods : Cell toxicity and survival of 709 different cell lines to > 140 different drugs were obtained from the Genomics of Drug Sensitivity in Cancer database (http://www.cancerrxgene.org/). All drugs are either FDA approved or in late phases of clinical trials for treatment of various cancers. The BAP1 mutational and copy number variation status of the cell lines were obtained from the COSMIC cell line project and cancer the cell line encyclopedia. The relative effectiveness of drugs on cell lines with and without BAP1 mutation was assessed by multivariable analysis of variances using the Genomic in Drug Sensitivity python package (GDSTools). Validation studies were carried out in-vitro on 8 cell lines from tumors associated with BAP1 loss including uveal melanoma, skin melanoma, mesothelioma/lung cancer and cholangiocarcinoma. Four of these 8 cell lines had confirmed BAP1 mutation or deletion.

Results : Out of the 709 cell lines available in the database 19 have BAP1 biallelic inactivation, 14 have heterozygous mutation, 15 have variants of uncertain significance and 660 have no alteration in BAP1. For cell lines with biallelic inactivation the mechanisms were either homodeletion (13 cell lines) or homozygous BAP1 mutation (6 cell lines). We focused our assessment on the optimal targeted therapy for cell lines with biallelic inactivation (i.e. total loss of BAP1) in comparison to cell lines with no BAP1 alterations. Three drugs showed statistically significant difference at a false discovery rate (FDR) of ≤ 25%. One of these three drugs was the PARP inhibitor rucaparib (effect size -0.87, pvalue=0.002, FDR 18%). Interestingly, another PARP inhibitor olaparib showed no significant selective effect (-0.13, pvalue=0.2, FDR 83%). The effects of these two PARP inhibitors were further validated in-vitro on BAP1 mutant and wild type cell lines. Studies of the effect of the two additional drugs are ongoing.

Conclusions : We identified novel potential targets for therapy of BAP1 mutated tumors. Our study suggests that a subset of PARP inhibitors could provide potential targeted therapy for BAP1 mutated tumors.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.