Potential Genetic Marker for Pancreatic Cancer Therapy Identified

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“Potential genetic marker identified for pancreatic cancer therapy”

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Researchers have discovered a genetic marker in pancreatic cancer that could provide the basis for the development of more effective, targeted treatments for pancreatic ductal adenocarcinoma (PDAC). The study was published in nature cancer.

Genetic markers for the treatment of pancreatic cancer

PDAC is known to be one of the deadliest and most aggressive cancers. Drugs such as poly-ADP-ribose polymerase (PARP) inhibitors have been approved by the FDA as standard therapy for PDAC patients with advanced (metastatic) disease. However, they are only effective in patients with hereditary diseases BRCA1/2 gene mutations. These genes are involved in the body’s response to damage in our DNA through a process called homologous recombination (HR). Mutations in these genes result in impaired damage repair. Only about 10% of PDAC patients have these mutations. “As a result, most patients miss out on this encouraging treatment strategy,” says Dr. Zhenken Lou, the senior author of the study.

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Nonetheless, Lou and colleagues at the Mayo Clinic Comprehensive Cancer Center discovered that another useful protein biomarker, known as methyltransferase 16 (METTL16), may exist that can be used to indicate whether a patient will benefit from treatment with PARP inhibitors could. Lou explains that increased METTL16 expression in PDAC tumor samples was associated with increased DNA damage, suggesting that “METTL16 suppresses DNA repair by interacting with a key DNA repair nuclease called MRE11,” which is what in turn, can lead to faster aging and an increased risk of cancer. Lou further emphasized that elevated METTL16 levels impair the HR process in some PDAC cases.

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Additional data from in vitro and in vivo Experiments show that high METTL16 expression is associated with increased sensitivity to PARP inhibitors, particularly in combination with the established chemotherapy drug gemcitabine.

Measuring METTL16 expression could become routine clinical practice

Taken together, these results suggest that PDAC patients with BRCA1/2 Mutations and/or increased METTL16 expression can both be targets for treatment with PARP inhibitors. Lou cautions that testing METTL16 expression in tumor tissue may eventually become routine for PDAC patients beginning treatment. “Additionally, the treatment strategy of gemcitabine in combination with PARP inhibitors may be more beneficial,” says Lou.

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The researchers also made some unexpected observations about the role of METTL16 in DNA repair. “Prior to our study, all documents on METTL16 showed its role in cellular activity as a function of RNA m6A methyltransferase activity. Second, we impressively demonstrated an inhibitory role of RNA and RNA-binding proteins in DNA repair.” They showed that RNA inhibits the formation of an inhibitory complex (METTL16-RNA-MRE11 complex) during the regulation of DNA repair conveyed. Overall, this suggests that RNA may also be important in the negative regulation of this process.

Relation: X Zeng, F Zhao, G Cui et al. METTL16 antagonizes MRE11-mediated terminal DNA resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nat Krebs. 2022;3(9):1088-1104. doi: 10.1038/s43018-022-00429-3

This article is a revision of a press release published by Mayo Clinic. The material has been edited for length and content.

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