Polymerase Theta (POLQ)

JCI165934. Epub ahead of print. PMID: 36976649.
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Polymerase Theta (POLQ)

The Role of Polymerase Theta (POLQ) in Synthetic Lethality in Homologous Recombination-Deficient (HRD) Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy. Recent genomic studies reveal that 20-25% of human PDA harbor recurrent mutations in genes involved in the DNA damage response, including BRCA1/2, PALB2, and ATM, which participate in homologous recombination (HR) repair. This subgroup of PDAs has emerged as a defined biological entity associated with a more aggressive disease course. Defects in HR in these tumors impart cells with a specific vulnerability to poly-ADP ribose polymerase (PARP) inhibitors and platinum-containing chemotherapy. Still, only a fraction of HR-defective patients responds to PARP inhibition. More so, many patients that initially respond often develop resistance and progress. Therefore, new therapies that can be effective against HR-defective PDA, alone or in combination with PARP inhibitors or other combinatorial regimens, are needed.

We have determined that inactivation of the HR pathway in PDA is associated with overexpression of polymerase theta (PolƟ, also known as POLQ). POLQ is a key enzyme that regulates the alternative non-homologous end-joining (alt-NHEJ) pathway of double-strand break (DSB) repair. In this study, in partnership with our collaborator Dr. Agnel Sfeir ( Skirball Institute, NYU) we will use a large portfolio of HR-defective PDA model systems, both murine and human, to interrogate the impact of POLQ levels on mutational load and genomic stability, tumor growth characteristics and the role of the alt-NHEJ pathway in mediating these effects. With POLQ inhibitors in clinical development, we seek to establish the pre-clinical data set that guide the use of these inhibitors for pancreatic cancer patients into the clinic.