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Cited by 888Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

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Bahar, Md Entaz, Kim, Hyun Joon, Kim, Deok Ryong·2023·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-023-01705-zPMC PMC10725898
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Abstract

Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS–RAF–MAPK kinase (MEK)–extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF -mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF -mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

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  • Aberrant activation of the RAS/MAPK pathway contributes to the development and progression of MM and other cancers.

    “The aberrant activation of RAS/MAPK pathway contributes to the development and progression of MM and other cancers [87, 88].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [87]

    The Introduction says RAS mutations constitutively activate MAPK signaling in many cancers, leading to uncontrolled proliferation; the physiological-functions section also links pathway activation to tumorigenesis and metastasis. The paper mentions multiple myeloma (MM) in discussions of pathway-targeted treatments, but the retrieved passages do not specifically establish that aberrant RAS/MAPK activation drives MM development or progression. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Bahar, M. E., Kim, H. J., & Kim, D. R.
Affiliations
Gyeongsang National University (KR)
Corresponding author
Kim, Deok Ryong
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-12-18
Volume
8
Issue
1
Pages
455-455
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-023-01705-z
PMC
PMC10725898
OpenAlex
W4389861133
Cited by
888
References
36
Citations by year
2026: 306 · 2025: 439 · 2024: 141 · 2019: 1 · 2016: 1
FWCI
23.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (RS-2023-00219399, RS-2023-00238051)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
RAS/MAPK pathway, RAF inhibitors, MEK inhibitors, RAF inhibitor resistance, autophagy, metastasis, chemoresistance, melanoma, non-small cell lung cancer, thyroid cancer, ERK signaling
MeSH terms
Humans, Lung Neoplasms, Melanoma, Mitogen-Activated Protein Kinase Kinases, Extracellular Signal-Regulated MAP Kinases, raf Kinases

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