Combination therapy shows therapeutic effects in RAS-mutant cancers

A new research suggests that combining PARP inhibitors with MEK inhibitors might be a therapeutic approach to RAS-mutant cancers.

The research was conducted by the University of Texas MD Anderson Cancer Center, the University of California, Baylor College of Medicine, and Harvard Medical School in the USA, in collaboration with Huazhong University of Science and Technology and Zhejiang University School of Medicine in China.

Findings were published by Science Translational Medicine on 31 May 2017.

For the past 3 decades, the Ras oncogene family has been studied extensively. Now we know that the RAS proteins, which are encoded by the Ras genes, control key signaling pathways that influence cellular proliferation, differentiation, and survival. Mutations in the Ras family of genes are present in 20-30% of all human cancers. In pancreatic cancer, the proportion is up to 95%.

Therefore, it is reasonable to think that inhibiting Ras activity may be an approach to treating these cancers. However, despite decades of research, most efforts to develop anti-Ras therapies have not been successful. Additionally, RAS-mutant cancers are usually resistant to conventional treatments, which is one of the major causes of unfavorable prognosis.

Previous studies indicate that RAS-mutant cancers appear to be resistant to PARP inhibitors, a new class of cancer drugs that is already approved to treat advanced ovarian cancer. In this study, the researchers unexpectedly found that addition of MEK inhibitors can reverse PARP inhibitor resistance in RAS-mutant tumors. MEK is a component of the RAS pathway, and several inhibitors of MEK are also clinically approved for cancer treatment. Using mouse models of RAS-mutant tumors such as pancreatic and ovarian cancer, the researchers demonstrated the effectiveness of the combination of MEK and PARP inhibitors. Combining MEK and PARP inhibitors evoked unanticipated, synergistic cytotoxic efforts, and these effects were dependent on the mutation status of BRCA1/2 and p53.

Overall, the study supports using the combination of MEK and PARP inhibitors to treat RAS-mutant tumors. This finding is significant for patients with RAS-mutant tumors, where there are few treatment options.
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