Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma

Mottini, Carla; Tomihara, Hideo; Carrella, Diego; Lamolinara, Alessia; Iezzi, Manuela; Huang, Justin K.; Amoreo, Carla Azzurra; Buglioni, Simonetta; Manni, Isabella; Robinson, Frederick S.; Minelli, Rosalba; Kang, Ya’an; Fleming, Jason B.; Kim, Michael P.; Bristow, Christopher A.; Trisciuoglio, Daniela; Iuliano, Antonella; Bufalo, Donatella Del; Bernardo, Diego di; Melisi, Davide; Draetta, Giulio; Ciliberto, Gennaro; Carugo, Alessandro; Cardone, Luca

doi:10.1158/0008-5472.can-19-0187

Cited by 13 publications

(19 citation statements)

References 57 publications

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“…These findings warrant further investigation, as they may support new strategies for implementing precision oncology in PDAC patients. For example, using a specific gene signature for KRAS dependency, recently led to the identification and validation of decitabine as a potent inhibitor of growth in KRAS-dependent pancreatic cancer cells and patient-derived xenograft models [ 29 ], an approach that is now being translated to the clinic.…”

Section: Introductionmentioning

confidence: 99%

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Luchini

Paolino

Mattiolo

et al. 2020

J Exp Clin Cancer Res

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

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Section: Introductionmentioning

confidence: 99%

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Luchini

Paolino

Mattiolo

et al. 2020

J Exp Clin Cancer Res

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“…Certain mutations of KRAS are associated with the response to drugs in PDAC cells (56). In PDAC associated with the KRAS mutation, decitabine therapy inhibits tumor growth (57). ARF6 is reported to be in close relationship with Ras pathway and its overexpression is related to unfavorable prognosis of PDAC patients (58).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

Liu

Liao

Wang

et al. 2020

Preprint

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Background: This study explored the prognostic significance of Glypican (GPC) family genes in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using data from The Cancer Genome Atlas (TCGA).Methods: A total of 112 PDAC patients from TCGA were included in the analysis.The relationship between overall survival and the expression of GPC family genes as well as basic clinical characteristics was analyzed using the Kaplan-Meier method with the log-rank test. Joint effects survival analysis was performed to further examine the relationship between GPC genes and prognosis. A prognosis nomogram was established based on clinical characteristics and prognosis-related genes. Prognosis-related genes were investigated by genome-wide co-expression analysis and gene set enrichment analysis (GSEA) to identify potential underlying mechanisms.Results: High expression of GPC2, GPC3, and GPC5 was significantly associated with favorable survival (log-rank P = 0.031, 0.021, and 0.028, respectively; adjusted P value = 0.005, 0.022, and 0.020, respectively), and joint effects analysis of these genes was effective for prognosis prediction. The prognosis nomogram was applied to predict the survival probability using the total score calculated. Genome-wide co-expression and GSEA analyses suggested that the GPC2 mechanisms affecting prognosis involved sequence-specific DNA binding, protein transport, cell differentiation and oncogenic signatures (KRAS, RAF, STK33, and VEGFA). GPC3 may be related to cell adhesion, angiogenesis, inflammatory response, signaling pathways like Ras, Rap1, PI3K-Akt, chemokine, GPCR, and signatures like cyclin D1, p53, PTEN. GPC5 may be involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway.Conclusion: GPC2, GPC3, and GPC5 expression may serve as prognostic indicators in PDAC, and the combination of these genes showed a higher efficiency for prognosis prediction.

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“…The goal of this review is to provide an overview of emerging molecular markers of K-RAS oncogene dependency, regardless of the genomic mutation status. Gene expression profile studies, in particular, allow to understand if the K-RAS pathway could be activated by mutations of the K-RAS gene or by many other mechanisms, and they help to deconstruct the K-RAS network contribution in tumor progression [ 45 , 48 , 54 ]. In addition, metabolomics studies identified pathways and metabolites that are specifically enriched in K-RAS-dependent PDAC to mediate a metabolic reprogramming relevant to tumor growth.…”

Section: Defining the K-ras Dependency In Pdacmentioning

confidence: 99%

“…The potential translational value of these scores was validated by Mottini et al [ 54 ] who showed that the gene expression signatures identified by Loboda and Singh showed a high correlation among them to classify K-RAS-dependent or K-RAS-independent PDAC cell lines according to signature similarity scores. In addition, the authors demonstrated, for the first time, that both genetic signatures derived by Loboda and Singh were able to identify a dependency on K-RAS in patient-derived xenograft (PDX) models of PDAC, which is a more reliable, patient-like experimental system, demonstrating the predictive capability of these two gene signatures identified by in-vitro cancer models.…”

Section: Scores Of K-ras Dependency Based On Gene Expression Signamentioning

confidence: 99%

“…Such discrepancy indicates the need for an accurate and robust validation for biomarkers of dependency, and it suggests that, besides in vitro-based studies, further validation of dependency biomarkers in a more physiological context such as in vivo tumor models is required. Moreover, the implementation of multiple transcriptional molecular scores for dependency would be of advantage for an accurate definition of K-RAS dependency, in particular when this information aims to predict drug response [ 54 ].…”

Section: Scores Of K-ras Dependency Based On Gene Expression Signamentioning

confidence: 99%

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Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers

Mottini

Cardone

2020

IJMS

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Oncogenic v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) plays a key role in the development and maintenance of pancreatic ductal adenocarcinoma (PDAC). The targeting of K-RAS would be beneficial to treat tumors whose growth depends on active K-RAS. The analysis of K-RAS genomic mutations is a clinical routine; however, an emerging question is whether the mutational status is able to identify tumors effectively dependent on K-RAS for tailoring targeted therapies. With the emergence of novel K-RAS inhibitors in clinical settings, this question is relevant. Several studies support the notion that the K-RAS mutation is not a sufficient biomarker deciphering the effective dependency of the tumor. Transcriptomic and metabolomic profiles of tumors, while revealing K-RAS signaling complexity and K-RAS-driven molecular pathways crucial for PDAC growth, are opening the opportunity to specifically identify K-RAS-dependent- or K-RAS-independent tumor subtypes by using novel molecular biomarkers. This would help tumor selection aimed at tailoring therapies against K-RAS. In this review, we will present studies about how the K-RAS mutation can also be interpreted in a state of K-RAS dependency, for which it is possible to identify specific K-RAS-driven molecular biomarkers in certain PDAC subtypes, beyond the genomic K-RAS mutational status.

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Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma

Cited by 13 publications

References 57 publications

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers

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