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Molecular Mechanisms and Therapies of Pancreatic Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 17214

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Special Issue Editors

Dr. Donatella Delle Cave

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Guest Editor

Institute of Genetics and Biophysics "A. Buzzati Traverso" (IGB-ABT), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: pancreatic cancer; cancer stem cells; tumor microenvironment; cancer metabolism; fibrosis; TGF-β signaling; target therapy; drug delivery systems
Special Issues, Collections and Topics in MDPI journals

Dr. Claudio Luchini

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Guest Editor

1. ARC-NET Applied Research on Cancer Center, University of Verona, 37134 Verona, Italy
2. Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy
Interests: pancreatic cancer; pancreatic ductal adenocarcinoma; precursors of pancreatic ductal adenocarcinoma; IPMN; variants of pancreatic ductal adenocarcinoma; molecular profile of pancreatic cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic cancer (PC) is one of the most aggressive solid malignancies, with an overall 5-year survival rate of ~8%, and it is predicted to become the second leading cause of cancer-related death by 2030. PC progression and metastasis are strongly influenced by metabolic stress imposed by the tumor microenvironment (TME) due to limited oxygen and nutrient supply and unfavorable pH. In this context, deregulation and reprogramming of energy metabolism are hallmarks of PC, which leads tumor cells to rewire their glucose, amino acid, and lipid metabolism on the basis of the bioenergetic and biosynthetic demands needed to survive and escape immunosurveillance. For this reason, exploiting cellular plasticity through targeted reprogramming of metabolic features in PC could lead to the generation of promising and novel selective therapeutic approaches for patients’ treatment.

This Special Issue was set up to encourage researchers to carry out studies on:

Reprogramming of the intracellular metabolism of nutrients (including glucose, amino acids and lipids) to impact PC progression;
Identification of novel pathways underlying metabolic reprogramming as therapeutic targets for PC;
Exploitation of cancer cell plasticity to modulate chemoresistance;
Shaping of the tumor microenvironment to sensitize cancer cells to chemotherapy.

Articles consisting exclusively of bioinformatics or computational analyses of public databases or pure clinical studies will not be accepted. Basic studies or translational studies including molecular characterizations of patients from real practice are welcome. Reviews are also appreciated.

Dr. Donatella Delle Cave
Dr. Claudio Luchini
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

pancreatic cancer
metabolism
cellular plasticity
tumor microenvironment
target therapy

Published Papers (13 papers)

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Editorial

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4 pages, 191 KiB

Open AccessEditorial

Emerging Therapeutic Options in Pancreatic Cancer Management

by Donatella Delle Cave

Int. J. Mol. Sci. 2024, 25(3), 1929; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031929 - 05 Feb 2024

Viewed by 753

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of <8% [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

Research

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10 pages, 1183 KiB

Open AccessArticle

PANC-1 Cell Line as an Experimental Model for Characterizing PIVKA-II Production, Distribution, and Molecular Mechanisms Leading to Protein Release in PDAC

by Antonella Farina, Sara Tartaglione, Adele Preziosi, Patrizia Mancini, Antonio Angeloni and Emanuela Anastasi

Int. J. Mol. Sci. 2024, 25(6), 3498; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063498 - 20 Mar 2024

Viewed by 580

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents a highly aggressive malignancy with a lack of reliable diagnostic biomarkers. Protein induced by vitamin K absence (PIVKA-II) is a protein increased in various cancers (particularly in hepatocellular carcinoma), and it has recently exhibited superior diagnostic performance in PDAC detection compared to other biomarkers. The aim of our research was to identify an in vitro model to study PIVKA-II production, distribution, and release in PDAC. We examined the presence of PIVKA-II protein in a panel of stabilized pancreatic cancer cell lines by Western blot analysis and indirect immunofluorescence (IFA). After quantitative evaluation of PIVKA-II in PaCa 44, H-Paf II, Capan-1, and PANC-1, we adopted the latter as a reference model. Subsequently, we analyzed the effect of glucose addiction on PIVKA-II production in a PANC-1 cell line in vitro; PIVKA-II production seems to be directly related to an increase in glucose concentration in the culture medium. Finally, we evaluated if PIVKA-II released in the presence of increasing doses of glucose is concomitant with the expression of two well-acknowledged epithelial–mesenchymal transition (EMT) markers (Vimentin and Snail). According to our experimental model, we can speculate that PIVKA-II release by PANC-1 cells is glucose-dependent and occurs jointly with EMT activation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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13 pages, 3020 KiB

Open AccessArticle

First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma

by Clayton S. Lewis, Charles Backman, Sabahat Ahsan, Ashley Cliff, Arthi Hariharan, Jen Jen Yeh, Xiang Zhang, Changchun Xie, Davendra P. S. Sohal and Vladimir Y. Bogdanov

Int. J. Mol. Sci. 2024, 25(5), 2580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25052580 - 23 Feb 2024

Viewed by 724

Abstract

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1’s ability to improve the efficacy of chemotherapy is significant and warrants further investigation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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14 pages, 3617 KiB

Open AccessArticle

Synergistic Anticancer Activity of Plumbagin and Xanthohumol Combination on Pancreatic Cancer Models

by Ranjith Palanisamy, Nimnaka Indrajith Kahingalage, David Archibald, Ilaria Casari and Marco Falasca

Int. J. Mol. Sci. 2024, 25(4), 2340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25042340 - 16 Feb 2024

Viewed by 823

Abstract

Among diverse cancers, pancreatic cancer is one of the most aggressive types due to inadequate diagnostic options and treatments available. Therefore, there is a necessity to use combination chemotherapy options to overcome the chemoresistance of pancreatic cancer cells. Plumbagin and xanthohumol, natural compounds isolated from the Plumbaginaceae family and Humulus lupulus, respectively, have been used to treat various cancers. In this study, we investigated the anticancer effects of a combination of plumbagin and xanthohumol on pancreatic cancer models, as well as the underlying mechanism. We have screened in vitro numerous plant-derived extracts and compounds and tested in vivo the most effective combination, plumbagin and xanthohumol, using a transgenic model of pancreatic cancer KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+). A significant synergistic anticancer activity of plumbagin and xanthohumol combinations on different pancreatic cancer cell lines was found. The combination treatment of plumbagin and xanthohumol influences the levels of B-cell lymphoma (BCL2), which are known to be associated with apoptosis in both cell lysates and tissues. More importantly, the survival of a transgenic mouse model of pancreatic cancer KPC treated with a combination of plumbagin and xanthohumol was significantly increased, and the effect on BCL2 levels has been confirmed. These results provide a foundation for a potential new treatment for pancreatic cancer based on plumbagin and xanthohumol combinations. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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13 pages, 2515 KiB

Open AccessArticle

Bile Microbiome Signatures Associated with Pancreatic Ductal Adenocarcinoma Compared to Benign Disease: A UK Pilot Study

by Nabeel Merali, Tarak Chouari, Julien Terroire, Maria-Danae Jessel, Daniel S. K. Liu, James-Halle Smith, Tyler Wooldridge, Tony Dhillon, José I. Jiménez, Jonathan Krell, Keith J. Roberts, Timothy A. Rockall, Eirini Velliou, Shivan Sivakumar, Elisa Giovannetti, Ayse Demirkan, Nicola E. Annels and Adam E. Frampton

Int. J. Mol. Sci. 2023, 24(23), 16888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242316888 - 28 Nov 2023

Cited by 1 | Viewed by 1675

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3–V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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19 pages, 6068 KiB

Open AccessArticle

IK Channel-Independent Effects of Clotrimazole and Senicapoc on Cancer Cells Viability and Migration

by Paolo Zuccolini, Raffaella Barbieri, Francesca Sbrana, Cristiana Picco, Paola Gavazzo and Michael Pusch

Int. J. Mol. Sci. 2023, 24(22), 16285; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242216285 - 14 Nov 2023

Cited by 2 | Viewed by 817

Abstract

Many studies highlighted the importance of the IK channel for the proliferation and the migration of different types of cancer cells, showing how IK blockers could slow down cancer growth. Based on these data, we wanted to characterize the effects of IK blockers on melanoma metastatic cells and to understand if such effects were exclusively IK-dependent. For this purpose, we employed two different blockers, namely clotrimazole and senicapoc, and two cell lines: metastatic melanoma WM266-4 and pancreatic cancer Panc-1, which is reported to have little or no IK expression. Clotrimazole and senicapoc induced a decrease in viability and the migration of both WM266-4 and Panc-1 cells irrespective of IK expression levels. Patch-clamp experiments on WM266-4 cells revealed Ca²⁺-dependent, IK-like, clotrimazole- and senicapoc-sensitive currents, which could not be detected in Panc-1 cells. Neither clotrimazole nor senicapoc altered the intracellular Ca²⁺ concentration. These results suggest that the effects of IK blockers on cancer cells are not strictly dependent on a robust presence of the channel in the plasma membrane, but they might be due to off-target effects on other cellular targets or to the blockade of IK channels localized in intracellular organelles. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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18 pages, 4390 KiB

Open AccessArticle

Targeting AHR Increases Pancreatic Cancer Cell Sensitivity to Gemcitabine through the ELAVL1-DCK Pathway

by Darius Stukas, Aldona Jasukaitiene, Arenida Bartkeviciene, Jason Matthews, Toivo Maimets, Indrek Teino, Kristaps Jaudzems, Antanas Gulbinas and Zilvinas Dambrauskas

Int. J. Mol. Sci. 2023, 24(17), 13155; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713155 - 24 Aug 2023

Cited by 3 | Viewed by 1193

Abstract

The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. AHR and ELAVL1 genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and AHR mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of AHR diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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12 pages, 1888 KiB

Open AccessArticle

Exosomal miRNA Biomarker Panel for Pancreatic Ductal Adenocarcinoma Detection in Patient Plasma: A Pilot Study

by Amy Makler and Waseem Asghar

Int. J. Mol. Sci. 2023, 24(6), 5081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065081 - 07 Mar 2023

Cited by 7 | Viewed by 1582

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming one of the leading causes of cancer-related deaths in the United States, and with its high mortality rate, there is a pressing need to develop sensitive and robust methods for detection. Exosomal biomarker panels provide a promising avenue for PDAC screening since exosomes are highly stable and easily harvested from body fluids. PDAC-associated miRNAs packaged within these exosomes could be used as diagnostic markers. We analyzed a series of 18 candidate miRNAs via RT-qPCR to identify the differentially expressed miRNAs (p < 0.05, t-test) between plasma exosomes harvested from PDAC patients and control patients. From this analysis, we propose a four-marker panel consisting of miR-93-5p, miR-339-3p, miR-425-5p, and miR-425-3p with an area under the curve (AUC) of the receiver operator characteristic curve (ROC) of 0.885 with a sensitivity of 80% and a specificity of 94.7%, which is comparable to the CA19-9 standard PDAC marker diagnostic. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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Review

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20 pages, 5206 KiB

Open AccessReview

Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy

by Kritisha Bhandari and Wei-Qun Ding

Int. J. Mol. Sci. 2024, 25(7), 3958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073958 - 02 Apr 2024

Viewed by 830

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a low 5-year overall survival rate. It is the third-leading cause of cancer-related deaths in the United States. The lack of robust therapeutics, absence of effective biomarkers for early detection, and aggressive nature of the tumor contribute to the high mortality rate of PDAC. Notably, the outcomes of recent immunotherapy and targeted therapy against PDAC remain unsatisfactory, indicating the need for novel therapeutic strategies. One of the newly described molecular features of PDAC is the altered expression of protein arginine methyltransferases (PRMTs). PRMTs are a group of enzymes known to methylate arginine residues in both histone and non-histone proteins, thereby mediating cellular homeostasis in biological systems. Some of the PRMT enzymes are known to be overexpressed in PDAC that promotes tumor progression and chemo-resistance via regulating gene transcription, cellular metabolic processes, RNA metabolism, and epithelial mesenchymal transition (EMT). Small-molecule inhibitors of PRMTs are currently under clinical trials and can potentially become a new generation of anti-cancer drugs. This review aims to provide an overview of the current understanding of PRMTs in PDAC, focusing on their pathological roles and their potential as new therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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25 pages, 1400 KiB

Open AccessReview

Copy Number Variations in Pancreatic Cancer: From Biological Significance to Clinical Utility

by Daisy J. A. Oketch, Matteo Giulietti and Francesco Piva

Int. J. Mol. Sci. 2024, 25(1), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010391 - 27 Dec 2023

Cited by 1 | Viewed by 1049

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, characterized by high tumor heterogeneity and a poor prognosis. Inter- and intra-tumoral heterogeneity in PDAC is a major obstacle to effective PDAC treatment; therefore, it is highly desirable to explore the tumor heterogeneity and underlying mechanisms for the improvement of PDAC prognosis. Gene copy number variations (CNVs) are increasingly recognized as a common and heritable source of inter-individual variation in genomic sequence. In this review, we outline the origin, main characteristics, and pathological aspects of CNVs. We then describe the occurrence of CNVs in PDAC, including those that have been clearly shown to have a pathogenic role, and further highlight some key examples of their involvement in tumor development and progression. The ability to efficiently identify and analyze CNVs in tumor samples is important to support translational research and foster precision oncology, as copy number variants can be utilized to guide clinical decisions. We provide insights into understanding the CNV landscapes and the role of both somatic and germline CNVs in PDAC, which could lead to significant advances in diagnosis, prognosis, and treatment. Although there has been significant progress in this field, understanding the full contribution of CNVs to the genetic basis of PDAC will require further research, with more accurate CNV assays such as single-cell techniques and larger cohorts than have been performed to date. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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20 pages, 1598 KiB

Open AccessReview

Locoregional Therapies and Remodeling of Tumor Microenvironment in Pancreatic Cancer

by Maria Caterina De Grandis, Velio Ascenti, Carolina Lanza, Giacomo Di Paolo, Barbara Galassi, Anna Maria Ierardi, Gianpaolo Carrafiello, Antonio Facciorusso and Michele Ghidini

Int. J. Mol. Sci. 2023, 24(16), 12681; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612681 - 11 Aug 2023

Cited by 2 | Viewed by 1461

Abstract

Despite the advances made in treatment, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal, even in the locoregional and locally advanced stages, with high relapse rates after surgery. PDAC exhibits a chemoresistant and immunosuppressive phenotype, and the tumor microenvironment (TME) surrounding cancer cells actively participates in creating a stromal barrier to chemotherapy and an immunosuppressive environment. Recently, there has been an increasing use of interventional radiology techniques for the treatment of PDAC, although they do not represent a standard of care and are not included in clinical guidelines. Local approaches such as radiation therapy, hyperthermia, microwave or radiofrequency ablation, irreversible electroporation and high-intensity focused ultrasound exert their action on the tumor tissue, altering the composition and structure of TME and potentially enhancing the action of chemotherapy. Moreover, their action can increase antigen release and presentation with T-cell activation and reduction tumor-induced immune suppression. This review summarizes the current evidence on locoregional therapies in PDAC and their effect on remodeling TME to make it more susceptible to the action of antitumor agents. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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19 pages, 1392 KiB

Open AccessReview

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

by Imke Stouten, Nadine van Montfoort and Lukas J. A. C. Hawinkels

Int. J. Mol. Sci. 2023, 24(10), 8707; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108707 - 13 May 2023

Cited by 4 | Viewed by 2640

Abstract

The lack of response to therapy in pancreatic ductal adenocarcinoma (PDAC) patients has contributed to PDAC having one of the lowest survival rates of all cancer types. The poor survival of PDAC patients urges the exploration of novel treatment strategies. Immunotherapy has shown promising results in several other cancer types, but it is still ineffective in PDAC. What sets PDAC apart from other cancer types is its tumour microenvironment (TME) with desmoplasia and low immune infiltration and activity. The most abundant cell type in the TME, cancer-associated fibroblasts (CAFs), could be instrumental in why low immunotherapy responses are observed. CAF heterogeneity and interactions with components of the TME is an emerging field of research, where many paths are to be explored. Understanding CAF–immune cell interactions in the TME might pave the way to optimize immunotherapy efficacy for PDAC and related cancers with stromal abundance. In this review, we discuss recent discoveries on the functions and interactions of CAFs and how targeting CAFs might improve immunotherapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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Other

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15 pages, 807 KiB

Open AccessOpinion

Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives

by Christos Adamopoulos, Donatella Delle Cave and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2024, 25(3), 1631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031631 - 28 Jan 2024

Cited by 2 | Viewed by 1675

Abstract

Pancreatic cancer represents a formidable challenge in oncology, primarily due to its aggressive nature and limited therapeutic options. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), the main form of pancreatic cancer, remains disappointingly poor with a 5-year overall survival of only 5%. Almost 95% of PDAC patients harbor Kirsten rat sarcoma virus (KRAS) oncogenic mutations. KRAS activates downstream intracellular pathways, most notably the rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling axis. Dysregulation of the RAF/MEK/ERK pathway is a crucial feature of pancreatic cancer and therefore its main components, RAF, MEK and ERK kinases, have been targeted pharmacologically, largely by small-molecule inhibitors. The recent advances in the development of inhibitors not only directly targeting the RAF/MEK/ERK pathway but also indirectly through inhibition of its regulators, such as Src homology-containing protein tyrosine phosphatase 2 (SHP2) and Son of sevenless homolog 1 (SOS1), provide new therapeutic opportunities. Moreover, the discovery of allele-specific small-molecule inhibitors against mutant KRAS variants has brought excitement for successful innovations in the battle against pancreatic cancer. Herein, we review the recent advances in targeted therapy and combinatorial strategies with focus on the current preclinical and clinical approaches, providing critical insight, underscoring the potential of these efforts and supporting their promise to improve the lives of patients with PDAC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer)

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