Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma

Cleary, James M.; Wolpin, Brian M.; Dougan, Stephanie K; Raghavan, Srivatsan; Singh, Harshabad; Huffman, Brandon M.; Sethi, Nilay; Nowak, Jonathan A.; Shapiro, Geoffrey I.; Aguirre, Andrew J.; D’Andrea, Alan D.

doi:10.1158/1078-0432.ccr-21-1367

Cited by 8 publications

(6 citation statements)

References 171 publications

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“…68 Furthermore, PARP inhibitor monotherapy has shown comparably low efficacy in breast and prostate cancers with PGVs in ATM, CHEK2, and other DNA damage repair genes; so, it seems dubious that this will be a viable therapeutic approach in GI cancers. [69][70][71][72] MSI-H/MMR-D status is certainly a reliable predictive somatic biomarker for benefit from immune checkpoint inhibitor therapy in individuals with advanced/metastatic cancers and is also present in the overwhelming majority of Lynch syndrome-associated malignancies. Lynch syndrome itself, however, is not predictive of benefit from immune checkpoint inhibitors.…”

Section: Context Key Objectivementioning

confidence: 99%

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Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Hampel

Yurgelun

2022

JCO

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Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration–approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.

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Section: Context Key Objectivementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Hampel

Yurgelun

2022

JCO

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“…For example, targeting DNA repair has become a legitimate therapeutic approach. This method uses PARP inhibitors to treat breast, ovarian, pancreatic and prostate cancers that have DNA repair deficiencies (89)(90)(91)(92)(93)(94)(95). Clinical research and development of small compounds that target key components of the DNA damage response and repair pathways, including DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and Rad3-related kinase (ATR), ATM and checkpoint kinase 1 (CHK1), have been accelerated (96).…”

Section: Underlying Mechanism Of Trip13-mediated Anticancer Drug Resi...mentioning

confidence: 99%

Targeting TRIP13 for overcoming anticancer drug resistance (Review)

Zhao,

Ye,

Jing

et al. 2023

Oncol Rep

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Cancer is one of the greatest dangers to human wellbeing and survival. A key barrier to effective cancer therapy is development of resistance to anti-cancer medications. In cancer cells, the AAA+ ATPase family member thyroid hormone receptor interactor 13 (TRIP13) is key in promoting treatment resistance. Nonetheless, knowledge of the molecular processes underlying TRIP13-based resistance to anticancer therapies is lacking. The present study evaluated the function of TRIP13 expression in anticancer drug resistance and potential methods to overcome this resistance. Additionally, the underlying mechanisms by which TRIP13 promotes resistance to anticancer drugs were explored, including induction of mitotic checkpoint complex surveillance system malfunction, promotion of DNA repair, the enhancement of autophagy and the prevention of immunological clearance. The effects of combination treatment, which include a TRIP13 inhibitor in addition to other inhibitors, were discussed. The present study evaluated the literature on TRIP13 as a possible target and its association with anticancer drug resistance, which may facilitate improvements in current anticancer therapeutic options.

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“…Evidence for increased immunogenicity of HRD tumors and upregulation of PD-L1 expression and STING pathway activation by PARPi supports the development of trials incorporating ICI combinations with HRD-targeting drugs (Table 1). 30 The development and exploitation of accurate preclinical models of HRD-PDAC will be essential for successful therapeutic targeting of the pathway.…”

Section: Future Hrd-targeting Strategiesmentioning

confidence: 99%

Moving the Needle on Precision Medicine in Pancreatic Cancer

O’Kane

Lowery²

2022

JCO

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The management of pancreatic ductal adenocarcinoma (PDAC) has posed a considerable challenge for decades, with incidence and mortality rates almost mirroring each other. Despite this, a deeper understanding of the complex biology inherent to PDAC has provided a roadmap for a more precise approach to treatment. PDAC deficient in homologous recombination repair and mismatch repair is a subgroup that should be identified in the clinic for a targeted approach. In addition, KRAS wild-type PDAC, occurring in approximately 10% of patients, is enriched in highly actionable alterations including fusions, underscoring the importance of integrative germline and somatic sequencing. Comprehensive sequencing efforts over the past decade have documented genomic- and transcriptomic-based classifiers, with the latter emerging as two main subtypes: the classical and basal-like, which are now being evaluated in clinical trials. Together with promising, innovative strategies to target KRAS mutations and their pleotropic effects, a new era of precision medicine in PDAC is on the horizon.

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Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma

Cited by 8 publications

References 171 publications

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Targeting TRIP13 for overcoming anticancer drug resistance (Review)

Moving the Needle on Precision Medicine in Pancreatic Cancer

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