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9.9
5.1
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Cells
Special Issues
Targeting RAS-Dependent Cancers
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Targeting RAS-Dependent Cancers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 7374

Special Issue Editor

Prof. Dr. Toshimitsu Yamaoka

E-Mail Website
Guest Editor
Advanced Cancer Translational Research Institute, Showa University, Tokyo 142-8555, Japan
Interests: Ras mutations; Ras targeting inhibitor; resistance to Ras inhibition; potential combination therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ras proteins play a major role in human cancers, including in pancreatic, lung, and colorectal cancers, and are the most frequently detected drivers of cancer-related gene alterations.

The main members of the RAS gene family, KRAS, HRAS, and NRAS, encode proteins that have a pivotal cytoplasmic role in cells. When RAS genes are mutated, cells grow uncontrollably and evade death signals. RAS mutations also confer resistance to cancer therapies in cells.

Developing strategies to block RAS function has been challenging; RAS proteins continue to be considered as virtually “undruggable” targets for therapy.

However, advances in technology and an improved understanding of RAS signaling and regulation have created opportunities to address this situation.

Recently, important advances have been achieved in directly targeted drugs, especially the KRASG12C inhibitor, such as AMG510 (sotorasib) and MRTX849 (adagrasib), with encouraging benefits demonstrated in clinical trials. As a first, AMG510 (sotorasib) was approved for cancer patients with the KRASG12C mutation.

This Special Issue aims to collect contributions on the current trends and advances in the field of cancer biology regarding novel therapeutic combinations, resistance to therapies, and cancer biomarkers. We solicit contributions, research papers, or reviews on all topics related to this research area.

Prof. Dr. Toshimitsu Yamaoka
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. Cells 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 2700 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
  • cancers
  • KRAS
  • HRAS
  • NRAS
  • therapeutic combinations
  • resistance to therapies
  • biomarkers
  • targeted drugs

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Published Papers (2 papers)

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13 pages, 640 KiB  
Article
KRAS G12D Mutation Subtype in Pancreatic Ductal Adenocarcinoma: Does It Influence Prognosis or Stage of Disease at Presentation?
by Henry Shen, Joanne Lundy, Andrew H. Strickland, Marion Harris, Michael Swan, Christopher Desmond, Brendan J. Jenkins and Daniel Croagh
Cells 2022, 11(19), 3175; https://doi.org/10.3390/cells11193175 - 10 Oct 2022
Cited by 23 | Viewed by 3247
Abstract
Background: KRAS G12D mutation subtype is present in over 40% of pancreatic ductal adenocarcinoma (PDAC), one of the leading global causes of cancer death. This retrospective cohort study aims to investigate whether detection of the KRAS G12D mutation subtype in PDAC patients [...] Read more.
Background: KRAS G12D mutation subtype is present in over 40% of pancreatic ductal adenocarcinoma (PDAC), one of the leading global causes of cancer death. This retrospective cohort study aims to investigate whether detection of the KRAS G12D mutation subtype in PDAC patients is a determinant of prognosis across all stages of disease. Methods: We reviewed the medical records of 231 patients presenting with PDAC at a large tertiary hospital, and compared survival using the Kaplan Meier, log-rank test and Cox proportional hazards regression model. Results: KRAS G12D mutation subtype was not significantly associated with poorer survival compared across the whole population of PDAC patients (p = 0.107; HR 1.293 95% CI (0.946–1.767)). However, KRAS G12D patients who were resectable had a shorter median survival time of 356 days compared to all other genotypes (median survival 810 days) (p = 0.019; HR 1.991 95% CI (1.121–3.537)). Conclusions: KRAS G12D patients who were resectable at diagnosis had shorter survival compared to all other PDAC patients. These data suggest that KRAS G12D may be a clinically useful prognostic biomarker of PDAC. Full article
(This article belongs to the Special Issue Targeting RAS-Dependent Cancers)
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17 pages, 5802 KiB  
Article
Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation
by Shigetoshi Nishihara, Toshimitsu Yamaoka, Fumihiro Ishikawa, Tohru Ohmori, Koichi Ando, Sojiro Kusumoto, Yasunari Kishino, Ryo Manabe, Yuki Hasebe, Hironori Sagara, Hitoshi Yoshida and Junji Tsurutani
Cells 2022, 11(14), 2201; https://doi.org/10.3390/cells11142201 - 14 Jul 2022
Cited by 6 | Viewed by 3533
Abstract
Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. [...] Read more.
Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. Herein, we investigated the mechanisms underlying the development of osimertinib resistance by treating NSCLC PC-9 cells (harboring an EGFR-activating mutation) with osimertinib, thereby developing five resistant cell lines, i.e., AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14. The amplification of wild-type EGFR in AZDR3 cells and wild-type EGFR and KRAS in AZDR6 cells was also studied. AZDR3 cells showed dependence on EGFR signaling, in addition to afatinib sensitivity. AZDR9 cells harboring KRASG13D showed sensitivity to MEK inhibitors. Furthermore, combination treatment with EGFR and IGF1R inhibitors resulted in attenuated cell proliferation and enhanced apoptosis. In AZDR11 cells, increased Bim expression could not induce apoptosis, but Bid cleavage was found to be essential for the same. A SHP2/T507K mutation was also identified in AZDR14 cells, and, when associated with GAB1, SHP2 could activate ERK1/2, whereas a SHP2 inhibitor, TNO155, disrupted this association, thereby inhibiting GAB1 activation. Thus, diverse osimertinib resistance mechanisms were identified, providing insights for developing novel therapeutic strategies for NSCLC. Full article
(This article belongs to the Special Issue Targeting RAS-Dependent Cancers)
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