BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
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Copyright: © 2019 . This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
A broad spectrum of tumors develops resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly (ADP-ribose) polymerase 1/2 proteins and DNA damage response genes including BRCA1, a factor involved in homologous recombination–mediated DNA repair and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. Inhibitors of CHK1 have been shown to enhance the anti-cancer effect of DNAdamaging compounds. Since, loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival.
