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Precision Medicine Approaches to Tackle RAS/RAF-Mutant Cancer

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

Deadline for manuscript submissions: closed (10 December 2023) | Viewed by 6296

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Special Issue Editors

Dr. Sandra Ortiz-Cuaran

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Guest Editor

Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, 69008 Lyon, France
Interests: lung adenocarcinoma; drug resistance; BRAF; HRAS; head and neck cancer

Dr. Moshe Elkabets

E-Mail Website
Guest Editor

The Shraga Segal Dept. of Microbiology, Immunology and Genetics Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
Interests: cancer therapeutics; tumor immunology; signaling and therapy resistance; head and neck cancer

Special Issue Information

Dear Colleagues,

RAS GTPases and RAF serine-threonine kinases constitute key regulators of signal transduction in cell survival and tumorigenesis. Gain-of-function mutations in these effectors have frequently been reported in human cancer.

In some cancer types, specifically in melanoma, the success of BRAF inhibitors reinforces the paradigm of using oncogenic-driver mutations as predictive markers to stratify patients for treatment using molecular- targeted therapies. However, years of clinical research in cancer patients have shown that not all BRAF mutations predict therapeutic responses and that patients who respond to treatment relapse to BRAF targeted therapy via diverse resistance mechanisms. Furthermore, in contrast to the well-studied BRAF mutation in cancer, less is known about the role of ARAF and CRAF alterations as driver mutations and their potential as therapeutic targets.

Although RAS inhibitors were elusive for a long time, the recent advent and use of KRAS_G12C inhibitors has shown marked clinical responses across multiple tumor types. However, as in the case of BRAF-mutant cancers, tumor responses to KRAS_G12C inhibitors are short-lived due to the development of resistance, which ultimately leads to clinical relapse. Multiple clinical trials are undertaken to further investigate the efficacy targeted therapies for the treatment of RAS- or RAF-driven cancers.

The purpose of this Special Issue is to present and discuss the current challenges of targeting RAF/RAS-mutant cancers to provide rationales of clinically relevant needs for the treatment of these patients. This Special Issue welcomes both original research articles and reviews by 30 April 2022.

Dr. Sandra Ortiz-Cuaran
Dr. Moshe Elkabets
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

MAPK pathway
BRAF
HRAS
NRAS
biomarkers
drug resistance
colon cancer
melanoma
head and neck cancer
lung cancer
thyroid cancer
pancreatic cancer
targeted therapy
clinical trials

Published Papers (3 papers)

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Review

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23 pages, 2355 KiB

Open AccessReview

Mutations in the Serine/Threonine Kinase BRAF: Oncogenic Drivers in Solid Tumors

by Paola Roa, Nicole Virginia Bremer, Valentina Foglizzo and Emiliano Cocco

Cancers 2024, 16(6), 1215; https://doi.org/10.3390/cancers16061215 - 20 Mar 2024

Viewed by 1284

Abstract

Since their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3% to 10% of reported cases. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches to the treatment of BRAF-mutant cancers have been taken. In this review, we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors. Full article

(This article belongs to the Special Issue Precision Medicine Approaches to Tackle RAS/RAF-Mutant Cancer)

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17 pages, 1151 KiB

Open AccessReview

Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling

by Samuel B. Reynolds, Kristen Pettit, Malathi Kandarpa, Moshe Talpaz and Qing Li

Cancers 2023, 15(18), 4654; https://doi.org/10.3390/cancers15184654 - 21 Sep 2023

Cited by 2 | Viewed by 2041

Abstract

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized clinically by cytopenias, fatigue, and splenomegaly stemming from extramedullary hematopoiesis. MF commonly arises from mutations in JAK2, MPL, and CALR, which manifests as hyperactive Jak/Stat signaling. Triple-negative MF is diagnosed in the absence of JAK2, MPL, and CALR but when clinical, morphologic criteria are met and other mutation(s) is/are present, including ASXL1, EZH2, and SRSF2. While the clinical and classic molecular features of MF are well-established, emerging evidence indicates that additional mutations, specifically within the Ras/MAP Kinase signaling pathway, are present and may play important role in disease pathogenesis and treatment response. KRAS and NRAS mutations alone are reportedly present in up to 15 and 14% of patients with MF (respectively), and other mutations predicted to activate Ras signaling, such as CBL, NF1, BRAF, and PTPN11, collectively exist in as much as 21% of patients. Investigations into the prevalence of RAS and related pathway mutations in MF and the mechanisms by which they contribute to its pathogenesis are critical in better understanding this condition and ultimately in the identification of novel therapeutic targets. Full article

(This article belongs to the Special Issue Precision Medicine Approaches to Tackle RAS/RAF-Mutant Cancer)

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Other

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8 pages, 1773 KiB

Open AccessBrief Report

Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019

by Jean-Bernard Auliac, Sophie Bayle, Pascal Do, Gwenaëlle Le Garff, Magali Roa, Lionel Falchero, Eric Huchot, Gilles Quéré, Gaëlle Jeannin, Anne-Cécile Métivier, Joëlle Hobeika, Florian Guisier and Christos Chouaid

Cancers 2020, 12(12), 3608; https://doi.org/10.3390/cancers12123608 - 2 Dec 2020

Cited by 13 | Viewed by 2384

Abstract

Dabrafenib plus trametinib combination is approved in Europe for BRAF V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring BRAF V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1–23.0) months and 25.5 (95% CI 16.6–not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1–23.2) months and median OS was 21.8 (95% CI 1.0–not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1–23.2) months and 25.5 (95% CI 16.6–not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with BRAF V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients. Full article

(This article belongs to the Special Issue Precision Medicine Approaches to Tackle RAS/RAF-Mutant Cancer)

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