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Newly discovered genetic marker could lead to precise treatment for pancreatic cancer
Researchers at the Mayo Clinic Comprehensive Cancer Center have identified a genetic marker that could lead to more effective and precise treatment for pancreatic ductal adenocarcinoma (PDAC). The researcher's findings are published in Nature Cancer. Pancreatic ductal adenocarcinoma is one of the deadliest cancers.” Dr. Zhenkun Lou, senior author of Paper According to Dr. According to Lou, poly-ADP-ribose polymerase inhibitors (PARPi) are now an FDA-approved option for standard maintenance therapy for patients with metastatic PDAC who have pathogenic BRCA1/2 germline mutations, but only about 10 percent of patients with PDAC have pathogenic mutations in the genes homologous recombination (HR). “As a result, most patients miss these...
Newly discovered genetic marker could lead to precise treatment for pancreatic cancer
Researchers at the Mayo Clinic Comprehensive Cancer Center have identified a genetic marker that could lead to more effective and precise treatment for pancreatic ductal adenocarcinoma (PDAC). The researcher's findings are published in Nature Cancer.
Pancreatic ductal adenocarcinoma is one of the deadliest cancers.”
Dr. Zhenkun Lou, senior author of Paper
According to Dr. According to Dr. Lou, poly-ADP-ribose polymerase inhibitors (PARPi) are now an FDA-approved option for standard maintenance therapy for patients with metastatic PDAC who have pathogenic BRCA1/2 germline mutations, but only about 10 percent of patients with PDAC have pathogenic mutations in homologous recombination (HR) genes. “As a result, most patients miss out on this encouraging treatment strategy,” says Dr. Lou.
In this study, Drs. Lou and his colleagues found that the protein METTL16 could be a new biomarker for PARPi treatment and that PDAC with increased 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 correlates with accumulated DNA damage in a PDAC microarray.”
He says elevated METTL16 can lead to HR DNA repair defects, which can lead to accelerated aging, disease or increased risk of cancer. “Our research showed that METTL16 suppresses DNA repair through interaction with an important DNA repair nuclease called MRE11.”
Dr. Lou and his colleagues found that METTL16 unexpectedly bound to MRE11 not through 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 METTL16 expression showed increased sensitivity to PARPi in both cell and mouse models, particularly in combination with gemcitabine,” says Dr. Lou.
Taken together, these results may indicate that in addition to PDAC with BRCA1/2 mutation, PDAC without BRCA1/2 mutation but with increased expression of METTL16 could be a target for PARPi treatment.
“In addition, the treatment strategy of gemcitabine in combination with PARPi may be more beneficial,” says Dr. Lou. He believes that immunochemical detection of METTL16 expression from tumors could eventually become a routine clinical practice for patients before starting treatment.”
Dr. Lou says his team unexpectedly found that METTL16 functions in DNA repair independently of its role in RNA m6A modification. "Prior to our study, all documents on METTL16 demonstrated its role in cellular activity depending on RNA m6A methyltransferase activity. Second, we strikingly demonstrated an inhibitory role of RNA and RNA-binding proteins in DNA repair." According to Dr. According to Dr. Lou, the role 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 DNA repair regulation, suggesting that RNA may also be a negative regulator of DNA repair.
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Reference:
Zeng, X., et al. (2022) METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Natural cancer. doi.org/10.1038/s43018-022-00429-3.