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“Identification of a potential genetic marker for pancreatic cancer treatment”
Researchers have discovered a genetic marker in pancreatic cancer that may lay the foundations for the development of more effective, targeted treatments for pancreatic ductal carcinoma (PDAC). The study was published in nature cancer.
Genetic markers for pancreatic cancer treatment
PDAC is known as one of the most deadly and dangerous types of cancer. Medications such as ADP polyribose polymerase (PARP) inhibitors have been approved by the US Food and Drug Administration as standard treatment for PDAC patients with advanced (metastatic) disease. However, it is only effective in patients with a genetic disease 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 impair damage repair. just around 10% of patients with PDAC They have these mutations. “This leaves most patients missing out on this encouraging treatment strategy,” he says Dr. Zinkin Lusenior author of the study.
However, Lou and his colleagues from Mayo Clinic Comprehensive Cancer Center He discovered that there might be another suitable biomarker for the protein, known as methyltransferase 16 (METTL16), which could be used to indicate whether a patient could benefit from a PARP inhibitor treatment. Lou shows that higher expression of METTL16 in PDAC tumor samples was associated with increased DNA damage, indicating that “METTL16 suppresses DNA repair by interacting with a key DNA repair endonuclease called MRE11,” which in turn may lead to faster aging and an increased risk of infection. diseases and cancer. Lou went on to highlight that increased levels of METTL16 in some cases of PDAC impair the HR process.
In addition, the data from in the laboratory And the in vivo Experiments have shown that higher expression of METTL16 is associated with increased sensitivity to PARP inhibitors, especially when combined with the well-established chemotherapy drug gemcitabine.
Measuring METTL16 expression can become a routine clinical practice
Together, these results suggest that PDAC patients have BRCA1/2 Mutations and/or elevated METTL16 expression may be targets for treatment with PARP inhibitors. Lou points out that testing METTL16 expression levels in tumor tissues may eventually become routine for PDAC patients who begin treatment. “In addition, a strategy of treating gemcitabine with PARP inhibitors may be more beneficial,” Lu explains.
The researchers also made some unexpected observations about the role of METTL16 in DNA repair. “Before our study, all documentation on METTL16 demonstrated its role in cellular activity depending on the activity of RNA m6A methyltransferase. Second, we strikingly revealed an inhibitory role for RNA and RNA-binding proteins in DNA repair.” They showed that RNA mediates the formation of An inhibitory complex (METTL16-RNA-MRE11 complex) during the regulation of DNA repair. Overall, this indicates that RNA can also be important in the negative regulation of this process.
Reference: Zeng X, Zhao F, Cui G et al. METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethal ability to inhibit PARP in pancreatic ductal adenocarcinoma. cancer nat. 2022; 3(9): 1088–1104. dui: 10.1038 / s43018-022-00429-3