Newswise – ROCHESTER, Minn. – Researchers from Mayo Clinic Comprehensive Cancer Center have identified a genetic marker that could lead to more effective precision treatment for pancreatic ductal adenocarcinoma (PDAC). The researcher’s findings are published in Nature Cancer.
“Pancreatic ductal adenocarcinoma is one of the deadliest cancers,” says the paper’s senior author Zhenkun Lou, Ph.D. Dr. Lou says poly-ADP-ribose-polymerase (PARPi) inhibitors are now an FDA-approved option for standard maintenance therapy for patients with metastatic PDAC who harbor a pathogenic germline BRCA1/2 mutations, only about 10 percent of patients with PDAC harbor pathogenic mutations in homologous recombination (HR) genes. “This leaves most patients deprived of this encouraging treatment strategy,” says Dr. Lou.
In this study, Dr. Lou and colleagues found that the METTL16 protein could be a novel biomarker for PARPi treatment, and that PDAC with high expression of METTL16 could benefit from PARPi treatment.
“METTL16 belongs to a family of factors that regulate RNA methylation, whose function in DNA repair is unclear,” says Dr. Lou. “We found that METTL16 expression was correlated with accumulated DNA damage in a PDAC microarray.” He says an elevated METTL16 can lead to defects in HR DNA repair, which can lead to accelerated aging, disease, or an increased risk of cancer. “Our research has shown that METTL16 suppresses DNA repair via interaction with a key DNA repair nuclease called MRE11.”
Dr. Lou and his colleagues found that METTL16 unexpectedly binds to MRE11 not through a direct protein-to-protein interaction, but through RNA. “Because METTL16 is highly expressed in a subset of PDAC and inhibits HR, PDAC cells with high expression of METTL16 showed increased sensitivity to PARPi in cell and mouse models, especially when combined with gemcitabine,” says Dr. Lou.
These results may collectively reveal that in addition to PDAC with BRCA1/2 mutation, PDAC without BRCA1/2 mutation, but with elevated expression of METTL16, may also be a target for PARPi treatment. “Additionally, the treatment strategy of gemcitabine plus PARPi may be more beneficial,” says Dr. Lou. He thinks that detection of METTL16 expression based on tumor immunochemistry could eventually become routine clinical practice for patients before starting treatment.
Dr. Lou says his team unexpectedly found that METTL16 functions in DNA repair independent of its role in modifying m6A RNA. “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. Dr. Lou says that the function of RNA in promoting DNA repair has been investigated in several studies. In this study, his team showed that RNA mediates the formation of an inhibitory complex (METTL16-RNA-MRE11 complex) in the regulation of DNA repair, suggesting that RNA could also be a negative regulator of DNA repair.
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