You should be able to rattle off the whole synthetic lethality bit between germline BRCA-mutated tumors and PARP inhibitors by now. If you can't, just know it basically hinges on the idea that BRCA-mutated tumors have finicky DNA repair. If you can throw another wrench into their DNA repair process, you can do some serious damage, say with something like lurbinectedin. No, it’s not a Native American-coined town off the Eerie canal. Lurbinectedin is an agent that blocks protein-coding gene transcription by irreversibly stalling RNA polymerase II. As with PARP inhibitors, this leads to an accumulation of double strand breaks that the BRCA-mutated tumor just can't handle. In this phase 2 trial, women with metastatic BRCA-mutated breast cancer were treated with Lurbinectedin with about a 40% response rate overall. But those with BRCA2-mutations, specifically, achieved a response rate of > 60%. This was thought to be related to the direct function of BRCA2 in repairing the kinds of R-loops induced by lurbinectedin. TBL: Lurbinectedin is an RNA polymerase II inhibitor that appears to be particularly effective in women with germline BRCA2-mutated metastatic breast cancer. | Cruz, J Clin Oncol 2018


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