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Molecular Genetics of Pancreatic Cancer and Translational Challenges

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 27363

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Prof. Dr. Lorenza Pastorino

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Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genova, Italy
Interests: melanoma; rare hereditary cancer syndrome; gene expression; functional analysis of mutations

Prof. Dr. Paola Ghiorzo

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Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
Interests: cancer genetics and genomics; molecular genetics; functional analysis; melanoma; pancreatic cancer; cancerogenesis; gene regulation; regulatory variants; hereditary cancers; somatic mutations
Special Issues, Collections and Topics in MDPI journals

Dr. William Bruno

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Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genova, Italy
Interests: rare cancers; hereditary cancers; genetic testing; molecular genetics; tumor heterogeneity; gene expression; functional genomics; genomic variations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies in industrialized countries and is predicted to become the second leading cause of cancer death by 2030.

Therefore, PDAC represents a challenge both in terms of early detection and treatment.

Many advancements have been made recently regarding the genetics of PDAC thanks to the current methodologies in the field of molecular genetics and genomics. These methods have the potential to improve our knowledge of the molecular mechanisms of the disease and to provide drug developers with new therapy targets. Despite these advancements, more research in needed.

An exhaustive comprehension of neoplastic initiation and progression events may require a broad approach, integrating concurrent events in cancer progression or susceptibility (genetics, epigenetics, RNA interference and noncodingRNA, transcriptomics).

Basic research studies on animal models, cell cultures, organoids, and liquid biopsy can also help elucidate mechanisms of tumorigenesis which are difficult to unravel with in vivo studies due to the frequently late diagnosis of PDAC or the scarce availability of appropriate biological samples.

In this Special Issue, we warmly welcome reviews, original research articles, or short communications about any novel findings that can elucidate the development of the PDAC through molecular genetics, at different levels, and their potential actionability, from inheritance to biomarkers to novel therapeutic targets.

Prof. Dr. Lorenza Pastorino
Prof. Dr. Paola Ghiorzo
Prof. Dr. William Bruno
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular genetics
genetic susceptibility
animal models
mechanisms of tumorigenesis
transcriptomic profiles
RNA interference
noncoding RNA
biomarkers
liquid biopsy
novel therapeutic targets

Published Papers (12 papers)

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Editorial

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4 pages, 206 KiB

Open AccessEditorial

Pancreatic Cancer: From Genetic Mechanisms to Translational Challenges

by Lorenza Pastorino, Paola Ghiorzo and William Bruno

Cancers 2023, 15(16), 4056; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15164056 - 11 Aug 2023

Viewed by 607

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies in industrialized countries, is predicted to become the second leading cause of cancer deaths by 2040 [...] Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

Research

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8 pages, 555 KiB

Open AccessArticle

Prevalence of a BRCA2 Pathogenic Variant in Hereditary-Breast-and-Ovarian-Cancer-Syndrome Families with Increased Risk of Pancreatic Cancer in a Restricted Italian Area

by Valentina Zampiga, Ilaria Cangini, Erika Bandini, Irene Azzali, Mila Ravegnani, Alessandra Ravaioli, Silvia Mancini, Michela Tebaldi, Gianluca Tedaldi, Francesca Pirini, Luigi Veneroni, Giovanni Luca Frassineti, Fabio Falcini, Rita Danesi, Daniele Calistri and Valentina Arcangeli

Cancers 2023, 15(7), 2132; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072132 - 03 Apr 2023

Cited by 2 | Viewed by 1433

Abstract

PVs and LPVs in BRCA1/2 genes are correlated to a high risk of developing breast cancer and/or ovarian cancer (Hereditary Breast and Ovarian Cancer syndrome, HBOC); additionally, in recent years, an increasing number of BRCA 1/2 variants have been identified and associated with pancreatic cancer. Epidemiologic studies have highlighted that inherited factors are involved in 10% to 20% of PCs, mainly through deleterious variants of BRCA2. The frequency of BRCA1/2 germline alterations fluctuates quite a lot among different ethnic groups, and the estimated rate of PVs/LPVs variants in Italian HBOC families is not very accurate, according to different reports. The aim of our study is to describe the prevalence of a BRCA2 PV observed in a selected cohort of HBOC patients and their relatives, whose common origin is the eastern coast of Emilia Romagna, a region of Italy. This study provides insight into the frequency of the variant detected in this area and provides evidence of an increased risk of pancreatic and breast cancer, useful for genetic counseling and surveillance programs. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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10 pages, 270 KiB

Open AccessArticle

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis

by Arianna Dal Buono, Laura Poliani, Luana Greco, Paolo Bianchi, Monica Barile, Valentina Giatti, Cristiana Bonifacio, Silvia Carrara, Alberto Malesci and Luigi Laghi

Cancers 2023, 15(6), 1852; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061852 - 20 Mar 2023

Cited by 3 | Viewed by 1877

Abstract

We investigate the prevalence of germline mutations in cancer predisposition genes in patients with pancreatic ductal adenocarcinoma (PDAC) or suspected related hereditary syndromes. Methods: we enrolled for NGS with an Illumina TrueSight Cancer panel comprising 19 CPGs and 113 consecutive subjects referred to cancer genetic clinics for metastatic PDAC, early onset PDAC, suspected hereditary syndrome, or positive family history. Results: Overall, 23 (20.1%) subjects were carriers of 24 pathogenetic variants (PVs). We found 9 variants in BRCA2 (37.5%), 6 in CDKN2A (25%), 3 in ATM (12.5%), 2 in BRCA1 (8.3%), 1 in CHEK2 (4.1%), 1 in PALB2 (4.1%), 1 in MITF (4.1%), and 1 in FANCM (4.1%). A double PV (BRCA1 plus BRCA2) was found in 1 subject. We observed a nearly 30% (16/55) mutational rate in the subgroup of subjects tested for the suspected syndromes (PDAC and other synchronous or metachronous tumors or an indicative family history), and the frequency was significantly higher than that in patients with only metastatic PDAC (p = 0.05). In our cohort, 39 variants of unknown significance (VUS) were identified, most of which (16/39, 41%) in genes belonging to the Lynch syndrome spectrum. Conclusion: A clinically relevant proportion of pancreatic cancer is associated with mutations in known predisposition genes. Guidelines instructing on an adequate selection for accessing genetic testing are eagerly needed. The heterogeneity of mutations identified in this study reinforces the value of using a multiple-gene panel in pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

22 pages, 7734 KiB

Open AccessArticle

Identification of Genes Associated with Liver Metastasis in Pancreatic Cancer Reveals PCSK6 as a Crucial Mediator

by Hang He, Shuman Zhang, Hai Yang, Pengyan Xu, Isabella Kutschick, Susanne Pfeffer, Nathalie Britzen-Laurent, Robert Grützmann, Deliang Fu and Christian Pilarsky

Cancers 2023, 15(1), 241; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010241 - 30 Dec 2022

Cited by 2 | Viewed by 1910

Abstract

Liver metastasis occurs frequently in patients with pancreatic cancer. We analyzed the molecular profiling in liver metastatic lesions aiming to uncover novel genes responsible for tumor progression. Bioinformatics analysis was applied to identify genes directing liver metastasis. CRISPR/Cas9 technology was used to knock out the candidate gene. Proliferation assays, colony formation assays, cell cycle analysis, migration assays, wound healing assays, Immunofluorescence analysis, and the tumor xenograft model of intrasplenic injection were adopted to evaluate the effects of PCSK6 inactivation on cell growth, migration and liver metastasis. GSEA and Western blot were used to investigate the corresponding signaling pathway. PCSK6 was one of the obtained liver-metastasis-related genes in pancreatic cancer. PCSK6 inactivation inhibited cell growth and cell migration, due to G0/G1 cell cycle arrest and the remodeling of cell–cell junctions or the cell skeleton, respectively. PCSK6 inactivation led to fewer counts and lower outgrowth rates of liver metastatic niches in vivo. The Raf-MEK1/2-ERK1/2 axis was repressed by PCSK6 inactivation. Accordingly, we found PCSK6 inactivation could inhibit cell growth, cell migration, and liver metastasis, and explored the role of the Raf-MEK1/2-ERK1/2 axis in PCSK6 inactivation. PCSK6-targeted therapy might represent a novel approach for combatting liver metastasis in pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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21 pages, 14497 KiB

Open AccessArticle

Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines

by Yixuan Ma, Benjamin Schulz, Nares Trakooljul, Moosheer Al Ammar, Anett Sekora, Sina Sender, Frieder Hadlich, Dietmar Zechner, Frank Ulrich Weiss, Markus M. Lerch, Robert Jaster, Christian Junghanss and Hugo Murua Escobar

Cancers 2022, 14(18), 4467; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184467 - 14 Sep 2022

Cited by 8 | Viewed by 2711

Abstract

Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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12 pages, 461 KiB

Open AccessArticle

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

by Alberto Puccini, Marta Ponzano, Bruna Dalmasso, Irene Vanni, Annalice Gandini, Silvia Puglisi, Roberto Borea, Malvina Cremante, William Bruno, Virginia Andreotti, Eleonora Allavena, Valentino Martelli, Fabio Catalano, Massimiliano Grassi, Maria Laura Iaia, Chiara Pirrone, Alessandro Pastorino, Giuseppe Fornarini, Stefania Sciallero, Paola Ghiorzo and Lorenza Pastorino Show full author list Hide full author list

Cancers 2022, 14(18), 4447; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184447 - 13 Sep 2022

Cited by 6 | Viewed by 2046

Abstract

Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A,BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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10 pages, 800 KiB

Open AccessArticle

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes

by Esteban Astiazaran-Symonds, Jung Kim, Jeremy S. Haley, Sun Young Kim, H. Shanker Rao, Regeneron Genetics Center, David J. Carey, Douglas R. Stewart and Alisa M. Goldstein

Cancers 2022, 14(13), 3257; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133257 - 02 Jul 2022

Cited by 8 | Viewed by 2366

Abstract

Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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19 pages, 1731 KiB

Open AccessArticle

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

by Mohammad Azhar Kamal, Imran Siddiqui, Cristina Belgiovine, Marialuisa Barbagallo, Valentina Paleari, Daniela Pistillo, Chiara Chiabrando, Silvia Schiarea, Barbara Bottazzi, Roberto Leone, Roberta Avigni, Roberta Migliore, Paola Spaggiari, Francesca Gavazzi, Giovanni Capretti, Federica Marchesi, Alberto Mantovani, Alessandro Zerbi and Paola Allavena

Cancers 2022, 14(11), 2653; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112653 - 27 May 2022

Cited by 8 | Viewed by 2534

Abstract

KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRAS^G12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I–IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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Review

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15 pages, 1672 KiB

Open AccessReview

Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer

by Bruna Dalmasso and Paola Ghiorzo

Cancers 2023, 15(13), 3486; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15133486 - 04 Jul 2023

Cited by 4 | Viewed by 1450

Abstract

Pancreatic adenocarcinoma is a highly aggressive disease with a poor prognosis. The reprogramming of energetic metabolism has long been implicated in pancreatic tumorigenesis and/or resistance to treatment. Considering that long non-coding RNA dysregulation has been described both in cancerogenesis and in the altered homeostasis of several metabolic pathways, metabolism-associated lncRNAs can contribute to pancreatic cancer evolution. The objective of this review is to assess the burden of lncRNA dysregulation in pancreatic cancer metabolic reprogramming, and its effect on this tumor’s natural course and response to treatment. Therefore, we reviewed the available literature to assess whether metabolism-associated lncRNAs have been found to be differentially expressed in pancreatic cancer, as well as whether experimental evidence of their role in such pathways can be demonstrated. Specifically, we provide a comprehensive overview of lncRNAs that are implicated in hypoxia-related pathways, as well as in the reprogramming of autophagy, lipid metabolism, and amino acid metabolism. Our review gathers background material for further research on possible applications of metabolism-associated lncRNAs as diagnostic/prognostic biomarkers and/or as potential therapeutic targets in pancreatic adenocarcinoma. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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17 pages, 1056 KiB

Open AccessReview

Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men

by Luana Greco, Federica Rubbino and Luigi Laghi

Cancers 2022, 14(23), 5797; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235797 - 24 Nov 2022

Cited by 7 | Viewed by 1843

Abstract

Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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25 pages, 2410 KiB

Open AccessReview

Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

by Adam S. Bryce, Stephan B. Dreyer, Fieke E. M. Froeling and David K. Chang

Cancers 2022, 14(21), 5302; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215302 - 28 Oct 2022

Cited by 8 | Viewed by 3432

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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16 pages, 1343 KiB

Open AccessReview

Targeting KRAS in PDAC: A New Way to Cure It?

by Qianyu He, Zuojia Liu and Jin Wang

Cancers 2022, 14(20), 4982; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14204982 - 11 Oct 2022

Cited by 14 | Viewed by 3879

Abstract

Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being “undruggable” due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRAS^G12C inhibitors; the covalent inhibitors bond to the switch-II pocket of the KRAS^G12C protein. The KRAS^G12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRAS^G12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRAS^G12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRAS^G12D/V and discuss the potential applications. Full article

(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)

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