Molecular Medicine Israel

A new road to cancer-drug resistance

The discovery of a mechanism that leads to cancer-therapy resistance highlights the many ways that tumour cells can adapt to survive — and reveals the limitations of categorizing patients by their gene mutations.

The development of resistance to cancer therapy is a major predictor of patient mortality. Therefore, understanding resistance mechanisms is key to improving therapeutic outcomes. Writing in Nature, He et al.1 report their discovery of a resistance mechanism in ovarian-cancer cells that contain a mutant version of the BRCA1 gene.

Mutations in BRCA1 and BRCA2 genes can cause breast and ovarian cancer by inactivating either of two major biological pathways that ensure genome stability. One of the pathways repairs DNA double-strand breaks through a process called homologous recombination2 (HR). The other process is called fork protection3,4, and safeguards newly synthesized DNA at structures called stalled forks that arise during DNA replication.

In HR repair, an essential bottleneck step is the processing (resection) of double-strand breaks by nuclease enzymes to produce single-stranded (ss) DNA. BRCA1 acts as a key regulator protein that coordinates the recruitment of the nucleases, which include the MRE11–RAD50–NBS1 protein complex. BRCA1 also has a second role in HR repair: it recruits BRCA2, which in turn loads the RAD51 protein onto the ssDNA. RAD51 then assists in the binding of the ssDNA to a complementary strand that serves as a template for error-free repair.

Cancer cells that have certain BRCA1 or BRCA2 mutations cannot repair double-strand breaks caused by anticancer drugs currently used in the clinic, and so die when treated. Such drugs include cisplatin and PARP inhibitors (PARPi, drugs that specifically target BRCA-mutant tumours by taking advantage of their break-repair defects5). However, cancer cells can acquire strategies to circumvent the drugs’ actions, causing resistance and limiting the use of these initially effective drugs.

In their rigorous study, He et al. used a gene-editing screening method6 to identify resistance mechanisms in BRCA1-mutant ovarian-cancer cells. A known resistance pathway in both BRCA1-mutant and BRCA2-mutant cells is the restoration of BRCA function by re-mutating the original BRCA mutation (see ref. 7, for example; Fig. 1a). A second mechanism is drug avoidance, in which a membrane protein pumps the drug out of the cell or reduces its uptake8. He and colleagues’ screen correctly identified a membrane protein implicated in the uptake of cisplatin by tumour cells as a contributor to resistance, verifying the suitability of the authors’ approach….

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