RAF-MEK-ERK pathway in cancer evolution and treatment
Abstract
The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAF V600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.
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Activated RAS proteins can interact with many downstream effector proteins, such as RAF kinase, son of sevenless (SOS), phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide dissociation stimulating factors (RalGDS), which regulate cell events such as cell proliferation and apoptosis.
“Activated RAS proteins can interact with many downstream effector proteins, such as RAF kinase, son of sevenless (SOS), phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide dissociation stimulating factors (RalGDS), which regulate cell events such as cell proliferation and apoptosis.323–325”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [325]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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“Around 200 low-frequency cancer-associated mutations have been described in BRAF [63].”
BackgroundHepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy
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Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer
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“Once activated, ERK1/2 translocates into the nucleus, where it phosphorylates numerous substrates [231].”
Natural products targeting the MAPK-signaling pathway in cancer: overview
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“The three RAF subtypes and downstream MEK1/2 and ERK1/2 from a constitute-signaling module to guide a series of physiological functions (Ullah et al. 2022).”
BackgroundSingh, M., Agarwal, V., Pancham, P., Jindal, D., Agarwal, S., Rai, S., Singh, S., & Gupta, V. (2024) · Degenerative Neurological and Neuromuscular Disease · doi:10.2147/dnnd.s445130 · Cited by 73 · see citing works
On a sugar high: Role of O-GlcNAcylation in cancer
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“As activation of the MAPK pathway is prevalent in many human cancers 31 , our results may point toward a universal biomarker opportunity for IL-17, not only across different MAPK genotypes, but also across different cancer entities.”
Jiang, J., Zou, Y., Xie, C., Yang, M., Tong, Q., Yuan, M.-M., Pei, X., Deng, S., Tian, M., Xiao, L., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.08.023 · Cited by 59 · see citing works
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“These oncogenic mutations often disrupt normal regulatory mechanisms, fostering uncontrolled cell growth and tumor formation (29).”
ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework
Timofeev, O. N., Giron, P., Lawo, S., Pichler, M., & Noeparast, M. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00554-5 · Cited by 59 · see citing works
“Essential effectors of this signaling cascade in humans fall into threetypesofeukaryoticproteinkinases:(1)HERfamilyReceptorTyrosine Kinases(RTKs,EGFR,HER2-4),RAFfamilyserine/threoninekinases(A/ B/CRAF),and(3)dualspeci fi city protein kinase families MEK (MEK1/2) and ERK (ERK1/2) 63 – 65 .”
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The Tumor Microenvironment: Signal Transduction
Zhang, X., Ma, H., Gao, Y., Liang, Y., Du, Y., Hao, S., & Ni, T. (2024) · Biomolecules · doi:10.3390/biom14040438 · Cited by 55 · see citing works
“Mutations in components of the RAS-RAF-MEK-ERK signaling pathway have been linked to different types of cancer [31–35].”
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“The RAF / MEK / ERK pathway regulates cell proliferation and survival, and BRAF mutations activate this pathway to create an immunosuppressive environment to allow uncontrolled tumor cell growth [22] .”
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
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“The RAF/MEK/ERK axis is active in over 40% of human cancers and is involved in physiological processes of cancer cells [53].”
The Multifaceted Role of miR-21 in Pancreatic Cancers
Chen, C., Demirkhanyan, L. H., & Gondi, C. S. (2024) · Cells · doi:10.3390/cells13110948 · Cited by 44 · see citing works
“Research has also shown that miR-21 expression promotes angiogenesis by regulating VRAP [114] and the RAF-MEK-ERK [115] pathway.”
BackgroundTargeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies
Wu, W., Xue, X., Chen, Y., Zheng, N., & Wang, J. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106456 · Cited by 43 · see citing works
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FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies
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“Those common features are not limited to the mechanism of action, but these receptors also share down-stream effectors and, as such, shared cellular events [3, 57, 108–110].”
BackgroundZhao, J., & Luo, Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095158 · Cited by 42 · see citing works
“Activation of ERK1/2 requires phosphorylation at threonine and tyrosine residues and inactivation through dephosphorylation [13,37,39,40].”
BackgroundRole of ENO1 and its targeted therapy in tumors
Li, Y., Liu, L., & Li, B. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05847-8 · Cited by 42 · see citing works
“The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway that participates in cell proliferation and survival [128].”
Derwich-Rudowicz, A., Sykutera, M., Bromińska, B., Rubiś, B., Ruchała, M., & Sawicka‐Gutaj, N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310952 · Cited by 40 · see citing works
“Grb2, in turn, recruits the GEF SOS protein, which facilitates the exchange of GDP to GTP on RAS proteins [96,102].”
BackgroundInfluentialLiu, W., Ding, Z., Tao, Y., Liu, S., Jiang, M., Yi, F., Wang, Z., Han, Y., Zong, H., Li, D., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02051-6 · Cited by 37 · see citing works
“The ERK pathway is the most important signaling cascade among all MAPK signal transduction pathways and plays a crucial role in the survival and development of tumor cells [36].”
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Withanolides: Promising candidates for cancer therapy
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Molecular changes driving low-grade serous ovarian cancer and implications for treatment
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“17 However, a recent multivariable analysis of tumors from a cohort of patients with low-grade serous ovarian carcinoma found that a MAPK tumor alteration was associated with improved overall survival.”
BackgroundNeurobiology of cancer: Adrenergic signaling and drug repurposing
Dong, Z.-K., Wang, Y., Li, W., & Jin, W. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108750 · Cited by 33 · see citing works
The role of acetylation and deacetylation in cancer metabolism
Wang, C., & Ma, X. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70145 · Cited by 31 · see citing works
“85 Both CBP and p300 can acetylate ERK1 at the N-terminal K72 site, and HDAC6 deacetylates ERK1/2.”
Ebrahimnezhad, M., Valizadeh, A., Majidinia, M., Tabnak, P., & Yousefi, B. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116833 · Cited by 29 · see citing works
RetractedRas isoform-specific expression, chromatin accessibility, and signaling
Nussinov, R., Zhang, M., Maloney, R., & Jang, H. (2021) · Biophysical Reviews · doi:10.1007/s12551-021-00817-6 · Cited by 28 · see citing works
“…localization and tumor growth (Garcia-Ibanez et al. 2020), Ras–ERK signaling (Zaballos et al. 2019) and MAPK inhibition (Heppner and Eck 2021; Ullah et al. 2021), isoform-specific differences in the effector binding regions (Nakhaeizadeh et al. 2016), and the recent contributions from…”
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“Increased extracellular signal-regulated kinase (ERK1/2) activity is a hallmark of cancer due to its pivotal role in promoting cell growth 16 – 18 .”
Wang, X., & Xiong, X. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s510972 · Cited by 27 · see citing works
“69 Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are essential for cancer cell survival.”
Zhang, J., Joshua, A. M., Li, Y., O’Meara, C. H., Morris, M. J., & Khachigian, L. M. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216633 · Cited by 27 · see citing works
o8G-modified circKIAA1797 promotes lung cancer development by inhibiting cuproptosis
Xu, H., Zhao, Q., Cai, D., Chen, X., Zhou, X., Gao, Y., Wu, J., Yuan, S., Li, D., Zhang, R., et al. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03365-z · Cited by 26 · see citing works
Pancreatic Cancer: Pathogenesis and Clinical Studies
Zhou, K., Liu, Y., Tang, C., & Zhu, H. (2025) · MedComm · doi:10.1002/mco2.70162 · Cited by 26 · see citing works
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“Active ERK translocates to the nucleus, where it phosphorylates various transcription factors and other nuclear proteins, leading to the expression of genes involved in cell proliferation, survival, and other cellular processes [123].”
BackgroundRAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 24 · see citing works
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TPI1 promotes MAPK / ERK ‐induced EMT , cell migration and invasion in lung adenocarcinoma
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“11,12,34 Activation of this pathway initiates a phosphorylation cascade, starting with the phosphorylation of receptor tyrosine kinases (RTKs), which, in turn, activate the Ras protein.”
BackgroundSong, M., Sun, W., Liu, Q., Wang, Z., & Zhang, H. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1306232 · Cited by 24 · see citing works
“Among the three RAF subtypes, BRAF is the most common mutation type (30).”
BackgroundGastric Cancer Signaling Pathways and Therapeutic Applications
Wu, M., Yuan, S., Liu, K., Wang, C., & Wen, F. (2024) · Technology in Cancer Research & Treatment · doi:10.1177/15330338241271935 · Cited by 24 · see citing works
“127,135 The RAF protein family includes BRAF, ARAF, and CRAF, with the BRAF gene mutation rate in cancer being 7%-10%.”
BackgroundMicroneedles-mediated drug delivery system for the diagnosis and treatment of melanoma
Liu, C., Zhao, Z., Lv, H., Yu, J., & Zhang, P. (2022) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2022.112818 · Cited by 24 · see citing works
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Oncel, S., Safratowich, B. D., Lindlauf, J. E., Liu, Z., Palmer, D. G., Briske‐Anderson, M., & Zeng, H. (2024) · Nutrients · doi:10.3390/nu16040529 · Cited by 24 · see citing works
GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors
Shilyansky, J. S., Chan, C. J., Xiao, S., Gribovskaja‐Rupp, I., Quelle, D. E., Howe, J. R., Dillon, J. S., & Ear, P. H. (2024) · Surgery · doi:10.1016/j.surg.2024.09.052 · Cited by 23 · see citing works
“36 The expression of the GLP-1R protein can be found in the nucleus, in cytoplasm, and on the membrane of NEN cells (Figure 1, C ).”
Natural products modulating MAPK for CRC treatment: a promising strategy
Zhou, L., Zhang, J., Zhao, K., Chen, B., & Sun, Z. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1514486 · Cited by 23 · see citing works
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“Given that receptor tyrosine kinases (RTKs) play important roles in the initiation of ERK cascade (65), whether RTKs contribute to FTO-mediated”
BackgroundGCN5–ERK lactylation–phosphorylation loop amplifies lactate-driven cancer progression
Huang, B., Jin, M., Cui, G., Wang, Z., Wang, F., Chen, M., Zhu, L., Li, Y., Yang, X., Li, R., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02107-8 · Cited by 24 · see citing works
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Tumour-agnostic kinase inhibitors
Adashek, J. J., Nikanjam, M., & Kurzrock, R. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01147-y · Cited by 21 · see citing works
“Three RAF isoforms — ARAF, BRAF and CRAF — and their downstream MEK1/2 and ERK1/2 kinases create a well-orchestrated signalling module 86 .”
The neuroscience of cancer: Focus on neuropeptidergic systems
Dong, Z.-K., Wang, Y., & Jin, W. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.03.025 · Cited by 22 · see citing works
“…stimulates down-stream effectors such as V-Raf murine sarcoma viral oncogene homolog B1, mitogen-activated protein kinase 1 and 2 (MEK1/2), and mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (ERK1/2), which is mainly associated with cell growth and proliferation 40 .”
Aktas, P. K., Baysal, İ., Ciftci, S. Y., & Arıca, B. (2023) · AAPS PharmSciTech · doi:10.1208/s12249-023-02634-4 · Cited by 21 · see citing works
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“Based on previous studies [17, 18] and our own results from antibody arrays [19], PI3K/AKT and MEK/ERK signaling pathways have emerged as two important signaling pathways involved in the development of GBM.”
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“However, genetic mutations in the HRAS gene can disrupt the balance of the RAS-MAPK pathway, leading to unregulated cellular proliferation and neoplastic transformation (Rezatabar et al., 2019; Ullah et al., 2022).”
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Background
- Authors
- Ullah, R., Yin, Q., Snell, A. H., & Wan, L.
- Affiliations
- Moffitt Cancer Center (US)
- Corresponding author
- Wan, Lixin
- Venue
- Seminars in Cancer Biology
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 85
- Pages
- 123-154
- ISSN
- 1044-579X (ISSN-L)
- OpenAlex
- W3160873367
- Cited by
- 553
- References
- 506
- Citations by year
- 2026: 123 · 2025: 164 · 2024: 173 · 2023: 69 · 2022: 19 · 2021: 5
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Seminars in Cancer Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Melanoma Research Alliance
- Florida Department of Health
- American Cancer Society
- 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
- Raf/MEK/ERK pathway, MAPK signaling, BRAF V600E mutation, Raf isoforms, MEK1/2, ERK1/2, Ras activation, receptor tyrosine kinase signaling, tumor evolution, cancer therapy, small molecule inhibitors, signaling crosstalk, oncogenic mutations
- MeSH terms
- Humans, Neoplasms, Signal Transduction, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf
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