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Updated: Jun 25, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Targeting RAF dimers in RAS mutant tumors: From biology to clinic
Huanhuan Yin1, Qiulin Tang1, Hongwei Xia1
1Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
Insights
Targeting RAF dimerization offers new hope for treating RAS-mutated cancers, overcoming limitations of current therapies. Type II RAF inhibitors, alone or combined with MEK/ERK inhibitors, show promise against these difficult-to-treat tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS mutations are prevalent in ~30% of cancers, associated with poor prognosis and limited therapeutic options.
- Targeting KRAS G12C mutations shows success, but effective treatments for other RAS mutations remain elusive.
- The MAPK pathway, downstream of RAS, is a key therapeutic target, particularly RAF kinases.
Purpose of the Study:
- To review the significance of RAF dimerization in RAS-mutated tumors and treatment resistance.
- To explore recent therapeutic strategies targeting RAF dimerization in RAS-mutated cancers.
Main Methods:
- Review of existing literature on RAS mutations, MAPK pathway signaling, and RAF inhibitor development.
- Analysis of clinical studies evaluating type II RAF inhibitors and combination therapies.
Main Results:
- First-generation RAF inhibitors are ineffective in RAS-mutated tumors due to paradoxical ERK activation from RAF dimerization.
- Type II RAF inhibitors show initial efficacy in RAS-mutated tumors by addressing RAF dimerization.
- Combination therapy with type II RAF inhibitors and MEK/ERK inhibitors demonstrates significant efficacy.
Conclusions:
- RAF dimerization is a critical mechanism driving resistance in RAS-mutated cancers.
- Type II RAF inhibitors represent a promising therapeutic avenue for RAS-mutated tumors.
- Combination strategies targeting RAF dimerization and downstream effectors offer potent anti-cancer activity.
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