Editors' ChoiceCancer therapy

New connections: Engineering DNA repair vulnerability to treat cancer

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Sci. Signal.  19 Jun 2018:
Vol. 11, Issue 535, eaau4685
DOI: 10.1126/scisignal.aau4685

Drugs that impair DNA repair broaden cancer sensitivity to common therapies.

Cancers are heterogeneous diseases for which therapeutic resistance is common. Finding ways to enhance the efficacy of currently approved therapeutics is desirable. Signaling by the p38α mitogen-activated protein kinase (MAPK) pathway promotes cell proliferation, and p38α inhibition suppresses tumor growth in some cancer models. Cánovas et al. report an additional role for p38α in breast cancer cells that might offer a new therapeutic opportunity in patients. Genetic deletion and inhibition assays in mice and cultured cells revealed that p38α coordinated the DNA damage response and limited chromosome instability by phosphorylating the DNA endonuclease and double-strand break (DSB)–repair protein CtIP. Hence, by causing DNA repair defects, p38α inhibitors enhanced the efficacy of commonly used taxane-based chemotherapies in mice bearing spontaneous breast tumors and patient-derived xenografts. In the Archives, Li et al. showed another example of how to generate DNA repair defects to enhance approved but ineffective therapies. The authors found that the androgen receptor inhibitor enzalutamide sensitized castration-resistant prostate cancer (CRPC) to olaparib, a poly(ADP)-ribose polymerase (PARP) inhibitor. Androgen receptor inhibitors are ineffective in CRPC, and PARP inhibitors are generally only effective in BRCA-mutant or otherwise homologous recombination (HR)–deficient tumors. However, pretreating mice bearing CRPC xenografts with enzalutamide decreased the expression of HR-related genes, including BRCA, which resulted in an HR-deficient phenotype, enabling synthetic lethality by subsequent treatment with the PARP inhibitor. These findings and their clinical utility are supported by a phase II trial reported by Clarke et al., in which combination therapy of the androgen pathway inhibitor abiraterone and olaparib improved survival compared with abiraterone alone in patients with metastatic CRPC. Thus, finding ways to cause DNA repair defects in tumor cells may not only improve our ability to kill them but also broaden the use of currently used tumor type–restricted drugs, such as PARP inhibitors.

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