DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research.

Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation

“…HR wild-type pancreatic cancer cell lines, e.g., Panc-1, MIAPaCa-2, and Panc02, were used to test whether our strategy would be efficacious for PDAC patients that do not harbor HR-related mutations. 45 Colony formation assay showed that in Panc-1, MIAPaCa-2, Panc02, and KPC-A548 cells, the half-maximal inhibitory concentration (IC 50 ) of Olaparib ranged from 1.0 to 20.6 μM, and the IC 50 values of AZD0156 were between 0.03 and 5.3 μM (Figure S7). The two drugs were first screened for their optimal dose ratios in the absence of electroporation (Figure 2A).…”

Dual Nucleosomal Double-Strand Breaks Are the Key Effectors of Curative Radiation Therapy

“…The non-homologically repairable damage includes plain NHEJ and all the mechanisms to the left of it in the lower half of the Figure 2a. The TP53 sensory layer between damage and repair is shown in more detail in Figure 3a describing the wide range of sensory proteins and cellular response mechanisms (Figure 2a developed from [1,9,33,34]).…”

“…The non-homologically repairable damage includes plain NHEJ and all the mechanisms to the left of it in the lower half of the Figure 2a. The TP53 sensory layer between damage and repair is shown in more detail in Figure 3a describing the wide range of sensory proteins and cellular response mechanisms (Figure 2a developed from [1,9,33,34]). The speed of the Ku-DNApk heterodimer complex and TP53 recruitment to a DNA DSB, a few seconds, makes it the most likely starting point of all DSBs absolutely necessary not to lose the right order in which the DNA ends belong together (horizontal blue arrow NHEJ->HR "switch" when p53 senses repair problems as in Figure 10 [1,4,9,17,27]).…”

“…5. These include mismatch repair as well as base and nucleotide excision repair [33,34], which are very capable of handling thousands of such damage events per Gy with high fidelity. At low doses and densities of DSBs, the non-homologous end-joining pathway (NHEJ) can handle the rejoining of local DNA ends quite well by using the Ku70 and Ku80 end clamps and the DNApk-Lig4 end-joining dimer complex (cf Figures 9 and 10, [2][3][4]7]).…”

Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs

“… 2, 3 ). Such molecular defects can advocate for promising targeted therapies ( 4 ) as transcriptomic signatures of high replication stress predict response to ATR and WEE1 inhibitors in preclinical models ( 5 ). More importantly, patients with germline mutations in the BRCA2 gene were recently found to benefit from first-line platinum-based FOLFIRINOX regimen followed by PARP inhibitors treatment ( 6 ).…”