Recent advances in precision medicine for pancreatic ductal adenocarcinoma

Hayashi, Hiromitsu; Higashi, Taishi; Miyata, Tatsunori; Yamashita, Yo‐ichi; Baba, Hideo

doi:10.1002/ags3.12436

Cited by 23 publications

(18 citation statements)

References 80 publications

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“…This transformation makes the cells more susceptible to pro-oncogenic events, thus promoting the onset of intra-epithelial neoplasias (PanINs), followed by sequential tumor suppressor gene mutations, leading to cancer progression [ 18 ]. It has been well-established that four main mutational events progressively accumulate in PDAC, driving the tumorigenesis: Kirsten rat sarcoma viral oncogene homolog (KRAS) activation, followed by cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 gene (TP53), and SMAD family member 4 (SMAD4) inactivation [ 5 , 19 , 20 ]. KRAS mutations show the highest frequency in PDAC, with more than 90% of tumors harboring oncogenic point mutations of this gene.…”

Section: Pancreatic Ductal Adenocarcinoma Heterogeneitymentioning

confidence: 99%

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Cortesi

Zanoni

Pirini

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.

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Section: Pancreatic Ductal Adenocarcinoma Heterogeneitymentioning

confidence: 99%

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Cortesi

Zanoni

Pirini

et al. 2021

IJMS

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“…Resistance mechanisms include deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, and resistance to apoptosis ( 6 ). Heterogeneity caused by admixture of tumor cells and stromal cells also produces chemoresistance and limits the targeted therapy of PDAC ( 7 ). Unfortunately, our knowledge of the genetic and biological backgrounds in this deadly disease has not yet been linked to improved patient survival.…”

Section: Introductionmentioning

confidence: 99%

Biological Significance of YAP/TAZ in Pancreatic Ductal Adenocarcinoma

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.

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“…However, the median OS in advanced-stage PAAD rarely exceeds 12 months ( 51 ). Recently, molecular markers have been employed to effectively select patients for therapy with specific anticancer agents ( 6 ). Oxaliplatin is a first-line drug in the FOLFIRINOX or GEMOX/XELOX regimen for PAAD patients.…”

Section: Discussionmentioning

confidence: 99%

“…During that period, numerous clinical trials of treatments for PAAD have failed, and treatment options remain limited ( 5 ). The molecular and functional heterogeneity of PAAD may partially explain the lack of progress in clinical treatment ( 6 ). Unfortunately, our knowledge of the biological diversity of PAAD and of the genomic aberrations associated with it has not yet been translated into meaningful endpoints in patient survival.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, deregulation of DNA repair pathways is associated with resistance to chemotherapy and radiotherapy ( 8 ). Based on genetic and molecular profiling, PAAD has been divided into several molecular subtypes ( 6 ). Molecular analysis has indicated that genetic alterations affect multiple signaling pathways in PAAD and that the DNA repair pathway is one of the key pathways involved ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

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Determination of a DNA repair-related gene signature with potential implications for prognosis and therapeutic response in pancreatic adenocarcinoma

et al. 2022

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BackgroundPancreatic adenocarcinoma (PAAD) is one of the leading causes of cancer death worldwide. Alterations in DNA repair-related genes (DRGs) are observed in a variety of cancers and have been shown to affect the development and treatment of cancers. The aim of this study was to develop a DRG-related signature for predicting prognosis and therapeutic response in PAAD.MethodsWe constructed a DRG signature using least absolute shrinkage and selection operator (LASSO) Cox regression analysis in the TCGA training set. GEO datasets were used as the validation set. A predictive nomogram was constructed based on multivariate Cox regression. Calibration curve and decision curve analysis (DCA) were applied to validate the performance of the nomogram. The CIBERSORT and ssGSEA algorithms were utilized to explore the relationship between the prognostic signature and immune cell infiltration. The pRRophetic algorithm was used to estimate sensitivity to chemotherapeutic agents. The CellMiner database and PAAD cell lines were used to investigate the relationship between DRG expression and therapeutic response.ResultsWe developed a DRG signature consisting of three DRGs (RECQL, POLQ, and RAD17) that can predict prognosis in PAAD patients. A prognostic nomogram combining the risk score and clinical factors was developed for prognostic prediction. The DCA curve and the calibration curve demonstrated that the nomogram has a higher net benefit than the risk score and TNM staging system. Immune infiltration analysis demonstrated that the risk score was positively correlated with the proportions of activated NK cells and monocytes. Drug sensitivity analysis indicated that the signature has potential predictive value for chemotherapy. Analyses utilizing the CellMiner database showed that RAD17 expression is correlated with oxaliplatin. The dynamic changes in three DRGs in response to oxaliplatin were examined by RT-qPCR, and the results show that RAD17 is upregulated in response to oxaliplatin in PAAD cell lines.ConclusionWe constructed and validated a novel DRG signature for prediction of the prognosis and drug sensitivity of patients with PAAD. Our study provides a theoretical basis for further unraveling the molecular pathogenesis of PAAD and helps clinicians tailor systemic therapies within the framework of individualized treatment.

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Recent advances in precision medicine for pancreatic ductal adenocarcinoma

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 23 publications

References 80 publications

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Biological Significance of YAP/TAZ in Pancreatic Ductal Adenocarcinoma

Determination of a DNA repair-related gene signature with potential implications for prognosis and therapeutic response in pancreatic adenocarcinoma

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