Cancers, Vol. 13, Pages 4716: Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Cancers, Vol. 13, Pages 4716: Determinants of Homologous Recombination Deficiency in Pancreatic Cancer Cancers doi: 10.3390/cancers13184716 Authors: Max M. Wattenberg Kim A. Reiss Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research

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Jieya Shao Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
AbstractPancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected p...
Source: Cancer and Metastasis Reviews - Category: Cancer & Oncology Source Type: research
Oncologist. 2021 Jul 26. doi: 10.1002/onco.13912. Online ahead of print.ABSTRACTFamilial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (1). The National Comprehensive Cancer Network (NCCN) recommends germline testing for patients diagnosed with PDAC and recommends platinum-based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC. (2) PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH) which results in ineffective DNA damage repair due to a lac...
Source: The Oncologist - Category: Cancer & Oncology Authors: Source Type: research
Clin Cancer Res. 2021 Jul 20:clincanres.1367.2021. doi: 10.1158/1078-0432.CCR-21-1367. Online ahead of print.ABSTRACTPancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicativ...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Source Type: research
DNA Repair (Amst). 2021 Apr 15;103:103116. doi: 10.1016/j.dnarep.2021.103116. Online ahead of print.ABSTRACTPancreatic cancer (PC) is among fatal malignancies, with a dismal prognosis and a low survival rate of 5-10%. In both sporadic and inherited PC, gene alterations, such as BRCA1/2, PALB2, and ATM, can occur frequently. Currently, surgery, chemo- and radio-therapy are the most common therapeutic strategies for treating this cancer. DNA damage response (DDR) establishes multiple pathways that eliminate DNA damage sites to maintain genomic integrity. Various types of cancers and age-related diseases are associated with D...
Source: DNA Repair - Category: Genetics & Stem Cells Authors: Source Type: research
DiscussionSystemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
Source: Journal of Hepato-Biliary-Pancreatic Sciences - Category: Gastroenterology Authors: Tags: REVIEW ARTICLE Source Type: research
CONCLUSION: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.PMID:33742489 | DOI:10.1002/onco.13758
Source: The Oncologist - Category: Cancer & Oncology Authors: Source Type: research
DiscussionSystemic treatment options for BTC has improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
Source: Journal of Hepato-Biliary-Pancreatic Sciences - Category: Gastroenterology Authors: Tags: REVIEW ARTICLE Source Type: research
This study suggests that rs2228528 in ERCC6 could be a potential predictor of response to FOLFIRINOX chemotherapy in patients with pancreatic cancer.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Abstract Advanced-stage gastrointestinal tumors have high mortality due to chemotherapy limitations. One of the causes of treatment failure is the presence of cancer stem cells (CSCs), which show resistance mechanisms against DNA damage, such as poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1). However, little is known about the relevance of PARP-1 in these tumor cells. Our purpose is to analyze the expression of PARP-1 in cancer cells and CSCs from gastrointestinal tumors, its relationship with the DNA damage repair process and its modulation by cytotoxic and PARP-1 inhibitors. We used pancreatic, liver ...
Source: Journal of Biosciences - Category: Biomedical Science Authors: Tags: J Biosci Source Type: research
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