Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.

Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines

“…Herein, we also evidenced that CBD and O 2 /O 3 , as single treatment or in combination, are able to reduce the expression of different genes of the PI3K pathway. PDAC, as above described, is also characterized by the acquisition of an anti-apoptotic phenotype, partially by inhibition of p53 and over-expression of anti-apoptotic proteins, which correlate with short survival and overall survival, particularly in Bcl-2 positive cases [ 55 , 56 ], and mutation in genes related to DNA damage response, such as BRCA1/2 [ 54 , 57 ]. Herein, we showed that CBD alone increased p53 and reduced BRCA2 gene expression.…”

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

“…For all this molecular evidence, ATM status analysis displays clinically relevant therapeutic implications. Indeed, similar to BRCA genetic alterations, ATM aberrations increase the efficacy of chemotherapeutic drugs which induce double strand DNA breaks, such as platinum drugs [67,68].…”