Molecular Biology and Therapeutic Perspectives for K-ras Mutant Cancers

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 10570

Special Issue Editor

Department of Molecular Biology, Umeå University, Umeå, Sweden
Interests: KRAS mutations; cancer metastasis; treatment resistance; novel KRAS inhibitor

Special Issue Information

Dear Colleagues,

Despite advances in personalized treatment, metastatic cancer and anticancer drug-induced treatment resistance remain major clinical challenges. Oncogenic KRAS mutation is a frequent event and is associated with metastasis in the major types of cancer including colorectal, lung, pancreatic, and breast cancer.  The development and utility of novel drugs that specifically target certain types of KRAS mutation in lung cancer have shed light on refining the tailored treatment of metastatic cancer, which harbors various types of KRAS mutation. However, the molecular mechanisms underlying the cancer metastasis and treatment resistance that are associated with various KRAS mutations in various types of cancer remain poorly understood.

We are pleased to invite you to submit a manuscript to this Special Issue, which aims to:

  • Strengthen the clinical and preclinical data on the collection and analyses of KRAS mutations and the alterations of KRAS-related pathways in various types of cancer, particularly metastatic cancer types such as colorectal, lung, pancreatic, breast, and prostate cancer.
  • Develop our understanding of the underlying mechanisms by which mutated KRAS and its associated pathways promote cancer cell invasive and metastatic potential and render cancer resistant to targeted therapy.
  • Design experimental models for improvement of tailored treatment of metastatic cancer using cancer cell lines and engineered in vitro and in vivo models.

Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Clinical and preclinical data on the collection and analyses of KRAS mutations in large patient cohorts.
  • The role of various types of common and rare KRAS mutations and the underlying mechanisms that drive cancer metastasis by using in vitro and in vivo models.

I look forward to receiving your contributions.

Prof. Dr. Jenny L. Persson
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.

Published Papers (4 papers)

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Research

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16 pages, 7444 KiB  
Article
K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer
by Heather Johnson, Amjad Ali, Xuhui Zhang, Tianyan Wang, Athanasios Simoulis, Anette Gjörloff Wingren and Jenny L. Persson
Cancers 2022, 14(21), 5322; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215322 - 28 Oct 2022
Cited by 2 | Viewed by 1459
Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line [...] Read more.
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality. Full article
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15 pages, 2149 KiB  
Article
In Silico Strategies for Designing of Peptide Inhibitors of Oncogenic K-Ras G12V Mutant: Inhibiting Cancer Growth and Proliferation
by Mehreen Ghufran, Haider Ali Khan, Mehran Ullah, Sabreen Ghufran, Muhammad Ayaz, Muhammad Siddiq, Syed Shams ul Hassan and Simona Bungau
Cancers 2022, 14(19), 4884; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194884 - 06 Oct 2022
Cited by 18 | Viewed by 2337
Abstract
Ras plays a pivotal function in cell proliferation and is an important protein in signal transduction pathways. Mutations in genes encoding the Ras protein drive the signaling cascades essential for malignant transformation, tumour angiogenesis, and metastasis and are responsible for above 30% of [...] Read more.
Ras plays a pivotal function in cell proliferation and is an important protein in signal transduction pathways. Mutations in genes encoding the Ras protein drive the signaling cascades essential for malignant transformation, tumour angiogenesis, and metastasis and are responsible for above 30% of all human cancers. There is evidence that N-Ras, K-Ras, and H-Ras play significant roles in human cancer. The mutated K-Ras protein is typically observed in malignant growths. Mutant K-Ras is the most common in lung, colon, and pancreatic cancers. The purpose of this research was to create peptides that inhibit K-Ras G12V. The crystal structure of the mutant K-Ras G12V-H-REV107 complex was obtained from a protein data bank. Further, we used a residue scan approach to create unique peptides from the reference peptide (H-REV107). AMBER molecular dynamics simulations were used to test the stability of the top four proposed peptides (based on binding free energies). Our findings showed that the top four selected peptides had stronger interactions with K-Ras than the reference peptide and have the ability to block the activation function of K-Ras. Our extensive analyses of binding affinities showed that our designed peptide possesses the potential to inhibit K-Ras and to reduce the progression of cancer. Full article
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Review

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25 pages, 1871 KiB  
Review
The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers
by Simon Manuel Tria, Matthew E. Burge and Vicki L. J. Whitehall
Cancers 2023, 15(8), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082375 - 19 Apr 2023
Cited by 5 | Viewed by 3413
Abstract
Colorectal cancer is one of the world’s most prevalent and lethal cancers. Mutations of the KRAS gene occur in ~40% of metastatic colorectal cancers. While this cohort has historically been difficult to manage, the last few years have shown exponential growth in the [...] Read more.
Colorectal cancer is one of the world’s most prevalent and lethal cancers. Mutations of the KRAS gene occur in ~40% of metastatic colorectal cancers. While this cohort has historically been difficult to manage, the last few years have shown exponential growth in the development of selective inhibitors targeting KRAS mutations. Their foremost mechanism of action utilizes the Switch II binding pocket and Cys12 residue of GDP-bound KRAS proteins in G12C mutants, confining them to their inactive state. Sotorasib and Adagrasib, both FDA-approved for the treatment of non-small cell lung cancer (NSCLC), have been pivotal in paving the way for KRAS G12C inhibitors in the clinical setting. Other KRAS inhibitors in development include a multi-targeting KRAS-mutant drug and a G12D mutant drug. Treatment resistance remains an issue with combination treatment regimens including indirect pathway inhibition and immunotherapy providing possible ways to combat this. While KRAS-mutant selective therapy has come a long way, more work is required to make this an effective and viable option for patients with colorectal cancer. Full article
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32 pages, 525 KiB  
Review
Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers
by Elona Cekani, Samantha Epistolio, Giulia Dazio, Marco Cefalì, Luciano Wannesson, Milo Frattini and Patrizia Froesch
Cancers 2022, 14(17), 4103; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174103 - 24 Aug 2022
Cited by 12 | Viewed by 2830
Abstract
In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with [...] Read more.
In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed. Full article
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