Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas
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BRAF(V600E) drives tumors by dysregulating ERK signaling. In these tumors, we show that high levels of ERK-dependent negative feedback potently suppress ligand-dependent mitogenic signaling and Ras function. BRAF(V600E) activation is Ras independent and it signals as a RAF-inhibitor-sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP, and generation of RAF-inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK pathway inhibition and antitumor activity.
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Recent research raises concerns about release of upstream RTK and Ras signals that activate reciprocal growth-promoting signaling pathways, such as PI3K/AKT/mTORC1, in preclinical melanoma models.
“recent research raises concerns about the release of upstream RTK and Ras signals that activate reciprocal growth-promoting signaling pathways, such as the PI3K/AKT/mTORC1 pathway in preclinical melanoma models.89”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [89]
RNA sequencing revealed that KRAS (G12C) inhibition causes significant repression of DUSP, SPRY, and PHLDA family genes known as negative regulators of the MAPK pathway.
“RNA sequencing revealed that KRAS (G12C) inhibition causes significant repression of DUSP, SPRY, and PHLDA family genes known as negative regulators of MAPK pathway [115, 116].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [115]
Potent inhibitors of RAS-RAF-MEK-ERK signaling silence ERK phosphorylation, but interruption of feedback circuits can cause rebound ERK activity.
“although potent inhibitors of RAS-RAF-MEK-ERK signaling efficiently silence ERK phosphorylation, interruption of feedback circuits can result in rebound of ERK activity (110)”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [110]
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Self-citation<i>BRAF</i> -Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape
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Protein–Protein Interactions: Emerging Oncotargets in the RAS-ERK Pathway
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“Pathway drug cocktail”: targeting Ras signaling based on structural pathways
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Overcoming Resistance to Drugs Targeting KRAS Mutation
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Overcoming adaptive resistance to KRAS inhibitors through vertical pathway targeting
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Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders
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Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells
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- Authors
- Lito, P., Pratilas, C. A., Joseph, E. W., Tadi, M., Halilovic, E., Zubrowski, M., Huang, A., Wong, W. L., Callahan, M. K., Merghoub, T., Wolchok, J. D., de Stanchina, E., Chandarlapaty, S., Poulikakos, P. I., Fagin, J. A., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 22
- Issue
- 5
- Pages
- 668-682
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3713778
- OpenAlex
- W2041255253
- Cited by
- 562
- References
- 45
- Citations by year
- 2026: 26 · 2025: 18 · 2024: 29 · 2023: 53 · 2022: 45 · 2021: 34 · 2020: 40 · 2019: 39 · 2018: 39 · 2017: 52 · 2016: 47 · 2015: 50 · 2014: 52 · 2013: 35 · 2012: 3
- FWCI
- 17.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 377 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (K08-CA127350, P01-CA129243)
- Dana Foundation
- Melanoma Research Alliance
- Harry J. Lloyd Charitable Trust
- 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
- BRAF V600E melanoma, RAF inhibitors, ERK signaling, negative feedback inhibition, RAF dimerization, Ras-GTP, MEK inhibitors, RAF inhibitor resistance, combination therapy
- MeSH terms
- Vemurafenib, Epidermal Growth Factor, Fibroblast Growth Factors, Humans, Indoles, Ligands, Melanoma, Membrane Proteins, Sulfonamides, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor, Receptors, Growth Factor, ras Proteins, Neuregulins, MAP Kinase Signaling System, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf
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