DNA Polymerase Theta Plays a Critical Role in Pancreatic Cancer Development and Metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of effective treatment, despite decades of intensive research, will become the second leading cause of cancer-related deaths by 2030. Step-wise acquisition of mutations, due to genomic instability, is considered to drive the development of PDAC; the KRAS mutation occurs in 95 to 100% of human PDAC, and is already detectable in early premalignant lesions designated as pancreatic intraepithelial neoplasia (PanIN). This mutation is possibly the key event leading to genomic instability and PDAC development. Our study aimed to investigate the role of the error-prone DNA double-strand breaks (DSBs) repair pathway, alt-EJ, in the presence of the KRAS G12D mutation in pancreatic cancer development. Our findings show that oncogenic KRAS contributes to increasing the expression of Polθ, Lig3, and Mre11, key components of alt-EJ in both mouse and human PDAC models. We further confirm increased catalytic activity of alt‑EJ in a mouse and human model of PDAC bearing the KRAS G12D mutation. Subsequently, we focused on estimating the impact of alt-EJ inactivation by polymerase theta (Polθ) deletion on pancreatic cancer development, and survival in genetically engineered mouse models (GEMMs) and cancer patients. Here, we show that even though Polθ deficiency does not fully prevent the development of pancreatic cancer, it significantly delays the onset of PanIN formation, prolongs the overall survival of experimental mice, and correlates with the overall survival of pancreatic cancer patients in the TCGA database. Our study clearly demonstrates the role of alt-EJ in the development of PDAC, and alt-EJ may be an attractive therapeutic target for pancreatic cancer patients.

Adaptive use of error‐prone DNA polymerases provides flexibility in genome replication during tumorigenesis

“…Accordingly, examinations of lung adenocarcinoma datasets from TCGA revealed an association between high Pol θ expression and an increased number of somatic mutations in tumors 50 . Interestingly, the abundance of Pol θ and other key TMEJ proteins (PARP1, Lig3, and Mre11) increases following the expression of oncogenic KRAS (KRAS G12D ) via a post‐transcriptional mechanism and, as a result, mutagenic TMEJ is encouraged 51 . Disrupting TMEJ by Pol θ deletion in mice expressing oncogenic KRAS delays the development of tumors, suggesting this pathway is a key player in KRAS‐induced tumorigenesis.…”

“… 50 Interestingly, the abundance of Pol θ and other key TMEJ proteins (PARP1, Lig3, and Mre11) increases following the expression of oncogenic KRAS (KRAS G12D ) via a post‐transcriptional mechanism and, as a result, mutagenic TMEJ is encouraged. 51 Disrupting TMEJ by Pol θ deletion in mice expressing oncogenic KRAS delays the development of tumors, suggesting this pathway is a key player in KRAS‐induced tumorigenesis. This is supported by data from TCGA which reveals that low Pol θ expression can increase survival in pancreatic adenocarcinoma patients with oncogenic KRAS mutations.…”

Multifaceted Nature of DNA Polymerase θ

“…Unique biochemical properties and functions of Pol θ suggest that it is a prospective target for cancer treatment. To date, many studies have supported the association of Pol θ expression/activity changes with disease development and progression, increased resistance to chemotherapeutic agents and poor prognosis in patients with breast, liver, prostate, esophagus, colon, lungs, stomach and pancreas cancer [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ].…”

“…Oncogenic KRAS mutations, driving malignant transformation of pancreatic cells, markedly upregulate the expression of TMEJ factors Mre11, Lig3, and Pol θ. TMEJ activation in murine and human cells with KRAS mutations resulted in the promotion of pancreatic intraepithelial neoplasia. Since TMEJ is the most preferred DNA repair pathway in pancreatic ductal adenocarcinoma cells, inhibition of Pol θ led to a slowing of disease progression and improved survival of animal models [ 96 ].…”