Identification of a potential genetic marker for the treatment of pancreatic cancer

Identification of a potential genetic marker for the treatment of pancreatic cancer

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“Identified a potential genetic marker for the treatment of pancreatic cancer”

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Researchers have discovered a genetic marker for pancreatic cancer that could lay the groundwork for developing more effective targeted treatments for pancreatic ductal adenocarcinoma (PDAC). The study is published in nature cancer.

Genetic markers for the treatment of pancreatic cancer

PDAC is known as 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 treatment for PDAC patients with advanced (metastatic) disease. However, they are only effective in patients with disease caused by an inherited condition. BRCA1/2 genetic mutations. These genes are involved in the body’s response to damage to our DNA through a process called homologous recombination (HR). Mutations in these genes lead to impaired damage repair. Only about 10% of PDAC patients have these mutations. “This leaves most patients deprived of this encouraging treatment strategy,” says Dr. Zhenken Lou, lead author of the study.

Nevertheless, Lou and colleagues at the Mayo Clinic Comprehensive Cancer Center discovered that another suitable protein biomarker may exist, known as methyltransferase 16 (METTL16), which can be used to indicate whether a patient might benefit from treatment. by PARP inhibitor. Lou explains that elevated METTL16 expression in PDAC tumor samples was associated with increased DNA damage, suggesting that “METTL16 suppresses DNA repair via interaction with a key DNA repair nuclease. DNA called MRE11″, which in turn can lead to faster aging and an increased risk of disease and cancer. Lou went on to point out that the increased levels of METTL16 in some cases of PDAC impairs the HR process.

Additionally, the data from in vitro and live experiments show that elevated METTL16 expression is associated with increased susceptibility to PARP inhibitors, especially when combined with gemcitabine, a well-established chemotherapeutic drug.

Measuring METTL16 expression could become routine clinical practice

Together, these results suggest that PDAC patients with BRCA1/2 both mutations and/or elevated expression of METTL16 may be targets for treatment with PARP inhibitors. Lou says testing METTL16 expression levels in tumor tissue could eventually become routine for PDAC patients starting treatment. “Additionally, the treatment strategy of gemcitabine combined with PARP inhibitors may be more beneficial,” says Lou.

The researchers also made unexpected observations regarding the role of METTL16 in DNA repair. “Before our study, all the papers regarding METTL16 showed its role in cellular activity as a function of m6A RNA methyltransferase activity. Second, we strikingly revealed an inhibitory role of RNA and RNA-binding proteins in DNA repair. They showed that RNA mediates the formation of an inhibitory complex (METTL16-RNA-MRE11 complex) when regulating DNA repair. Taken together, this suggests that RNA may also play an important role in negatively regulating this process.

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

This article is a reprint of a Press release issued by Mayo Clinic. Material has been edited for length and content.

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