The biological underpinnings of therapeutic resistance in pancreatic cancer

Beatty, Gregory L.; Werba, Gregor; Lyssiotis, Costas A.; Simeone, Diane M.

doi:10.1101/gad.348523.121

Cited by 77 publications

(44 citation statements)

References 219 publications

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“…Pancreatic cancer is characterized by a hostile TME, consisting of dense fibrosis, immunoregulatory stromal cells, robust myeloid cell infiltration and a paucity of T cells [ 98 ]. Moreover, features of the TME play key roles in regulating sensitivity to chemotherapy, radiotherapy and immunotherapy [ 99 , 100 ]. The balance and geography of myeloid and lymphoid elements in the TME is a critical element which associates with clinical outcomes [ 101 , 102 ].…”

Section: Tumor Intrinsic and Extrinsic Determinants Of Hrdmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Cancers

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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.

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Section: Tumor Intrinsic and Extrinsic Determinants Of Hrdmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Cancers

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“…PDAC emerges from an original indolent pancreatic intraepithelial lesion (PanINs) that persist in a poorly aggressive forms for many years. Progression of PanINs to highly aggressive, frankly invasive, and metastatic PDACs is very frequently associated to p53 mutations (75% of cases) [ 35 – 37 ] and directs a complex rearrangement of the microenvironment [ 38 – 40 ]. This latter staged neoplastic forms become symptomatic, but even when surgically approachable they generally manifest too late to carry positive prognosis.…”

Section: Introductionmentioning

confidence: 99%

NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network

et al. 2021

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Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value. We identified NUAK2 and RCan2 whose p53 mutant GOF-dependent regulation was further validated in pancreatic cancer cellular model. Our data demonstrated that p53R270H can physically bind RCan2 gene locus in regulatory regions corresponding to the chromatin permissive areas where known binding partners of p53 mutant, such as p63 and Srebp, bind. Overall, starting from clinically relevant data and progressing into experimental validation, our work suggests NUAK2 and RCan2 as novel candidate players of the p53 mutant pro-tumorigenic network whose prognostic and therapeutic interest might attract future studies.

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“…Gemcitabine is a pyrimidine analogue (2',2'-difluoro-2'-deoxycytidine, dFdC; Gemzar®) widely prescribed to treat a variety of solid tumours [67] . It has been used for decades as the first-line treatment for metastatic PDAC, and it is still commonly used for PDAC patients in combination with nab-paclitaxel or as monotherapy in patients who are unfit for combination regimens, as mentioned above [7,9] .…”

Section: Synergistic Interaction With Gemcitabine Is Associated With An Increase Of Hent1 Mrna Expressionmentioning

confidence: 99%

“…Because of its hydrophilic nature, gemcitabine requires facilitated or active transport for cellular uptake, which is mediated by membrane nucleoside transporters, including the human concentrative nucleoside transporter-3 and hENT1. The latter has been evaluated in several preclinical and clinical studies as a potential determinant of gemcitabine efficacy in PDAC [9] .…”

Section: Synergistic Interaction With Gemcitabine Is Associated With An Increase Of Hent1 Mrna Expressionmentioning

confidence: 99%