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Cancers
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RAS Signaling Pathway in Cancer Therapy
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RAS Signaling Pathway in Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 16 August 2024 | Viewed by 5353

Special Issue Editor

Dr. Matthias Drosten

E-Mail Website
Guest Editor
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer (CSIC-USAL), Salamanca, Spain
Interests: MAPK signaling; RAS signaling; lung cancer; mouse models; mechanisms of drug resistance

Special Issue Information

Dear Colleagues,

Mutations in one of the RAS genes are found in a quarter of all human cancers. Since their discovery, researchers have attempted to develop therapeutic strategies to inhibit RAS oncoproteins, either directly or indirectly; however, it was not until 2021 that the first inhibitor that blocks one of the mutant isoforms of KRAS (KRASG12C) in its inactive state was finally approved. Moreover, other strategies are currently being developed, including those that inhibit this oncoprotein in its active form or approaches to target other mutant isoforms. Given that RAS signaling plays a critical role in several cellular activities such as cell proliferation, a deeper understanding of RAS signaling in cancer, but also in development or homeostasis, is urgently required to further improve the therapeutic options for patients with tumors harboring RAS mutations.

The scope of this Special Issue is to further advance our understanding of the unique requirements for RAS signaling in distinct contexts such as tumor initiation, growth, or maintenance. Genetic studies in particular, although not exclusively, have the potential to uncover novel vulnerabilities that may ultimately expand the therapeutic options for patients with acquired or even intrinsic resistance. More importantly, genetic studies can also provide knowledge regarding essential requirements for RAS signaling in more universal contexts, with the final goal being to keep the therapy-related toxicities as low as possible.

Dr. Matthias Drosten
Guest Editor

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

  • RAS signaling
  • MAPK pathway
  • RAS effectors
  • KRAS inhibitors
  • resistance
  • drug combinations
  • tumor growth mechanisms
  • signaling pathways
  • toxicity

Published Papers (3 papers)

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Research

12 pages, 1639 KiB  
Article
Focus on RAS Codon 61 Mutations in Metastatic Colorectal Cancer: A Retrospective Analysis
by Francesco Schietroma, Annunziato Anghelone, Giustina Valente, Viria Beccia, Giulia Caira, Alexia Spring, Giovanni Trovato, Armando Di Bello, Anna Ceccarelli, Laura Chiofalo, Serena Perazzo, Maria Bensi, Angelo Minucci, Andrea Urbani, Luigi Maria Larocca, Michele Basso, Carmelo Pozzo, Lisa Salvatore, Maria Alessandra Calegari and Giampaolo Tortora
Cancers 2024, 16(5), 988; https://doi.org/10.3390/cancers16050988 - 29 Feb 2024
Viewed by 743
Abstract
RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1–4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed [...] Read more.
RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1–4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed to investigate the clinical phenotype and prognostic performance of codon 61 RAS-mutated mCRC. Fifty patients with codon 61 RAS-mutated mCRC treated at our institution between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wild-type mCRCs (648 patients) were used as comparators. The endpoint for prognostic assessment was overall survival (OS). Metastatic involvement of the peritoneum or ovary was significantly more frequent in codon 61 RAS-mutated mCRC compared to codon 61 RAS wild-type (54 vs. 28.5%), non-codon 61 RAS-mutated (35.6%), BRAF V600E-mutated (25%), and RAS/BRAF wild-type (20.5%) cohorts. At a median follow up of 96.2 months, the median OS for codon 61 RAS-mutated patients was significantly shorter compared to RAS/BRAF wild-type (26.9 vs. 36.0 months, HR 0.56) patients, while no significant difference was observed compared to non-codon 61 RAS-mutated and BRAF V600E-mutated patients. We showed a negative prognostic impact and a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary. Full article
(This article belongs to the Special Issue RAS Signaling Pathway in Cancer Therapy)
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26 pages, 5728 KiB  
Article
Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib
by Aoife Nolan, Cinzia Raso, Walter Kolch, Alex von Kriegsheim, Kieran Wynne and David Matallanas
Cancers 2023, 15(16), 4141; https://doi.org/10.3390/cancers15164141 - 17 Aug 2023
Cited by 1 | Viewed by 2651
Abstract
RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in KRAS. These mutations were thought to cause the constitutive activation [...] Read more.
RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in KRAS. These mutations were thought to cause the constitutive activation of KRAS, but recent findings showed that some mutants can cycle between active and inactive states. This observation, together with the development of covalent KRASG12C inhibitors, has led to the arrival of KRAS inhibitors in the clinic. However, most patients develop resistance to these targeted therapies, and we lack effective treatments for other KRAS mutants. To accelerate the development of RAS targeting therapies, we need to fully characterise the molecular mechanisms governing KRAS signalling networks and determine what differentiates the signalling downstream of the KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild-type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allows us to map the signalling network mediated by the different KRAS proteins. Using this approach, we characterised how the interactome of KRAS wild-type and mutants is regulated by the clinically approved KRASG12C inhibitor Sotorasib. In addition, we identified novel crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules. Full article
(This article belongs to the Special Issue RAS Signaling Pathway in Cancer Therapy)
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19 pages, 2639 KiB  
Article
K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness
by Ganesh babu Manoharan, Christina Laurini, Sara Bottone, Nesrine Ben Fredj and Daniel Kwaku Abankwa
Cancers 2023, 15(12), 3087; https://doi.org/10.3390/cancers15123087 - 07 Jun 2023
Cited by 1 | Viewed by 1363
Abstract
Recent data suggest that K-Ras4B (hereafter K-Ras) can drive cancer cell stemness via calmodulin (CaM)-dependent, non-canonical Wnt-signalling. Here we examined whether another Ca2+-binding protein, the CaM-related centrin1, binds to K-Ras and could mediate some K-Ras functions that were previously ascribed to [...] Read more.
Recent data suggest that K-Ras4B (hereafter K-Ras) can drive cancer cell stemness via calmodulin (CaM)-dependent, non-canonical Wnt-signalling. Here we examined whether another Ca2+-binding protein, the CaM-related centrin1, binds to K-Ras and could mediate some K-Ras functions that were previously ascribed to CaM. While CaM and centrin1 appear to distinguish between peptides that were derived from their classical targets, they both bind to K-Ras in cells. Cellular BRET- and immunoprecipitation data suggest that CaM engages more with K-Ras than centrin1 and that the interaction with the C-terminal membrane anchor of K-Ras is sufficient for this. Surprisingly, binding of neither K-Ras nor its membrane anchor alone to CaM or centrin1 is sensitive to inhibition of prenylation. In support of an involvement of the G-domain of K-Ras in cellular complexes with these Ca2+-binding proteins, we find that oncogenic K-RasG12V displays increased engagement with both CaM and centrin1. This is abrogated by addition of the D38A effector-site mutation, suggesting that K-RasG12V is held together with CaM or centrin1 in complexes with effectors. When treated with CaM inhibitors, the BRET-interaction of K-RasG12V with centrin1 was also disrupted in the low micromolar range, comparable to that with CaM. While CaM predominates in regulating functional membrane anchorage of K-Ras, it has a very similar co-distribution with centrin1 on mitotic organelles. Given these results, a significant overlap of the CaM- and centrin1-dependent functions of K-Ras is suggested. Full article
(This article belongs to the Special Issue RAS Signaling Pathway in Cancer Therapy)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Preclinical therapeutic efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR inhibition in neuroblastoma
Authors: Stacey Stauffer; Jacob S. Roth; Edjay R. Hernandez; Joshua T. Kowalczyk; Nancy E. Sealover; Norris Lam; Katie E. Hebron; Xiaolin Wan; Amy James; Kristine A. Isanogle; Lisa A. Riffle; Lilia Ileva; Xiaoling Luo; Jin-Qiu Chen; Noemi Kedei; Robert L. Kortum; Haiyan Lei; Jack F. Shern; Joseph D. Kalen; Elijah F. Edmondson; Matthew D Hall; Simone Difilippantonio; Carol J. Thiele; Marielle E Yohe
Affiliation: National Cancer Institute
Abstract: Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Pre-clinical studies indicate these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the com-bination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

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