Potential Genetic Marker for Pancreatic Cancer Therapy Identified
Researchers have discovered a genetic marker in pancreatic cancer that may lay the foundations for developing more effective, targeted treatments for pancreatic ductal adenocarcinoma (PDAC). The study is published in Nature Cancer.
Genetic markers for pancreatic cancer treatment
PDAC is known as one of the most lethal and aggressive cancers. Drugs such as poly-ADP ribose polymerase (PARP) inhibitors have been approved by the FDA as a standard therapy for PDAC patients with advanced (metastatic) disease. However, they are only effective in patients with disease caused by hereditary 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 lead to impaired damage repair. Only about 10% of PDAC patients have these mutations. “This leaves most patients missing out on this encouraging treatment strategy,” says Dr. Zhenken Lou, the senior author of the study.
Nevertheless, Lou and colleagues from the Mayo Clinic Comprehensive Cancer Center discovered that another suitable protein biomarker may exist, known as methyltransferase 16 (METTL16), which may be used to indicate if a patient could benefit from PARP inhibitor treatment. 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 called MRE11,” which in turn may lead to faster aging and increased risk of disease and cancer. Lou went on to highlight that increased METTL16 levels in some PDAC cases impairs the HR process.
Additionally, data from in vitro and in vivo experiments show that high METTL16 expression is associated with increased sensitivity to PARP inhibitors, particularly when combined with the well-established chemotherapeutic drug gemcitabine.
Measuring METTL16 expression could become routine clinical practice
Together, these results suggest that PDAC patients with BRCA1/2 mutations and/or elevated METTL16 expression may both be targets for treatment with PARP inhibitors. Lou indicates that testing for levels of METTL16 expression in tumor tissue may eventually become routine for PDAC patients starting treatment. “In addition, the treatment strategy of gemcitabine combined with PARP inhibitors may be more beneficial,” Lou elaborates.
The researchers also made some unexpected observations surrounding the role of METTL16 in DNA repair. “Prior to our study, all documents regarding METTL16 showed its role in cellular activity depending on the RNA m6A 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) during regulation of DNA repair. Overall, this suggests that RNA could 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 lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nat Cancer. 2022;3(9):1088-1104. doi: 10.1038/s43018-022-00429-3