Editors' ChoiceCancer

Doubling down on tumor suppressor deletion

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaba2903
DOI: 10.1126/scitranslmed.aba2903

Abstract

Codeletion of BRCA2 and RB1 increases prostate cancer sensitivity to PARP inhibitor therapy.

Unlike many cancer types that are driven by a small number of hotspot mutations in genes, such as the oncogene HRAS or the tumor suppressor TP53, prostate cancer is driven by somatic copy number changes that affect large segments of chromosomes encompassing cancer genes. Molecular characterization of large metastatic prostate cancer cohorts has shown that although some tumors have a portion of chromosome 13 deleted that span either of the tumor suppressors RB1 or BRCA2, other cancers have lost both genes as part of a single deletion event. Chakraborty et al. examined two independent datasets and found that patients with tumors harboring co-loss of BRCA2 and RB1 experienced shorter time to disease progression compared with single losses, and co-loss was more frequent in metastases compared with primary tumors.

Testing the effects of suppressing and deleting BRCA2, RB1, or both BRCA2 and RB1 in prostate cancer cell lines, Chakraborty and colleagues observed an epithelial-to-mesenchymal transition (EMT) phenotype exemplified by changes to cell morphology, increased migratory and invasive properties, and altered expression of EMT genes encoding E-cadherin and Snail. Organoids derived from patients with metastatic prostate cancer also demonstrated an EMT phenotype when BRCA2 and RB1 were codeleted. However, aggressive properties were also observed when only one copy of both genes was suppressed, indicating that the combined effect of codeletion was more potent than single deletions of either gene.

Recently, clinical trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in prostate cancer have demonstrated efficacy in tumors with inactivation of both copies of DNA-damage repair genes, including BRCA2. The authors tested whether PARP inhibitor treatment reduced tumor cell viability depending on the status of BRCA2 and RB1. Prostate cancer cell lines with both BRCA2 and RB1 suppressed were more sensitive to PARP inhibitors than when only one gene was suppressed, and prostate cancer organoids were similarly more sensitive, even if they harbored a single codeletion, leaving the remaining copy of chromosome 13 intact. This finding has implications for biomarker-driven clinical trials of PARP inhibitors: A single copy loss of BRCA2, when codeleted with RB1, may make more patients eligible to receive these potent therapies.

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