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Introduction
With a five-year survival rate of 10% across all stages, pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide [1, 2]. The high mortality rate and poor prognosis of PDAC stem from the absence of clinical signs in the disease's early stages, the high recurrence rate, and substantial resistance to treatment modalities, including chemotherapy and radiation. Many clinical studies on PDAC treatments have been unsuccessful, and thus alternative treatment options are limited. The molecular and functional heterogeneity of PDAC may partly explain the lack of clinical therapeutic advancements.
Genomic instability is defined as a high frequency of harmful alterations in the genomic structure that result from a compromised DNA repair response, which is a hallmark of cancers. The emergence of several cancers has been linked to the silencing of or to harmful mutation in tumor suppressor genes, including checkpoint and DNA repair genes such as P53, P16, and ataxia telangiectasia mutated (ATM). The DNA damage response (DDR), which encompasses signaling and repair, is necessary for genome stability. Multiple DDR mechanisms, including direct reversal, base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair, and double-strand break repair, can occur [3, 4–5]. DDR pathways play a role in tumor development and progression and the tumor response to treatment [6]. Certain studies have shown a correlation between DDR deficiency and the stimulation of anticancer immunity via the activation of the classical cGAS-STING pathway. In addition to causing alterations in the tumor immune milieu, DDR anomalies also impact the therapeutic efficacy of immunological checkpoint inhibitors (ICIs) [7]. Moreover, the main factor limiting the response to single drugs in cancer therapy is tumor acquisition of resistance. Drug resistance may result from the interplay of DDR mechanisms.
Personalized medicine for PDAC is a relatively new research area, and there are currently no predictive biomarkers available. Several studies have been performed to investigate numerous possible biomarkers for predicting the response to different treatments (chemotherapy, immunotherapy, or targeted therapy) and the prognosis of PDAC. The most recognized biomarkers are BRCA1 and BRCA2 mutations, which are linked to advantages from platinum-based therapies and PARP inhibitors (PARPis). The only approved targeted maintenance treatment for pancreatic cancer is olaparib, a DNA-damaging drug designed for hormone...