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Cited by 84Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingChemotherapy-related skin toxicity

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BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling

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Vin, Harina, Ojeda, Sandra S, Ching, Grace, Leung, Marco L, Chitsazzadeh, Vida, Dwyer, David W, Adelmann, Charles H, Restrepo, Monica, Richards, Kristen N, Stewart, Larissa R, Du, Lili, Ferguson, Scarlett B, Chakravarti, Deepavali, Ehrenreiter, Karin, Baccarini, Manuela, Ruggieri, Rosamaria, Curry, Jonathan L, Kim, Kevin B, Ciurea, Ana M, Duvic, Madeleine, Prieto, Victor G, Ullrich, Stephen E, Dalby, Kevin N, Flores, Elsa R, Tsai, Kenneth Y·2013·eLife
DOI 10.7554/elife.00969PMC PMC3814616
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Abstract

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies.

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  • A literature search revealed an MKK4 inhibitory potential of the clinically approved BRAFV600E inhibitor vemurafenib.

    “As an exploitable ATP-binding pocket model could not be established, a literature search focusing on reported off-target profiles of protein kinase inhibitors was conducted and revealed an MKK4 inhibitory potential of the clinically approved BRAFV600E inhibitor vemurafenib.18”

    From First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure (2024) · cites this paper as [18]

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Metadata

Authors
Vin, H., Ojeda, S. S., Ching, G., Leung, M. L., Chitsazzadeh, V., Dwyer, D. W., Adelmann, C. H., Restrepo, M., Richards, K. N., Stewart, L. R., Du, L., Ferguson, S. B., Chakravarti, D., Ehrenreiter, K., Baccarini, M., Ruggieri, R., Curry, J. L., Kim, K. B., Ciurea, A. M., Duvic, M., Prieto, V. G., Ullrich, S. E., Dalby, K. N., Flores, E. R., & Tsai, K. Y.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Texas at Austin (US)
  • Max Perutz Labs (AT)
  • Feinstein Institute for Medical Research (US)
Corresponding author
Tsai, Kenneth Y
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2013-11-05
Volume
2
Pages
e00969-e00969
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.00969
PMC
PMC3814616
OpenAlex
W2158315886
Cited by
84
References
5
Citations by year
2026: 5 · 2025: 2 · 2024: 9 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 9 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 12 · 2015: 10 · 2014: 4
FWCI
3.88
Type
journal article
Language
en
Update notices
correction (2026-02-19)
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Phaidra (Universität Wien) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Skin Association
  • Elsa U Pardee Foundation
  • University of Texas MD Anderson IRG Program
  • DX Biosciences Cancer Research Fund
  • National Cancer Institute (CA16672)
  • National Institutes of Health (GM059802, CA167505)
  • Welch Foundation ((F-1390))
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
  • Health Sciences › Medicine › Dermatology › Chemotherapy-related skin toxicity
Keywords
BRAF inhibitors, vemurafenib, dabrafenib, cutaneous squamous cell carcinoma, off-target kinase inhibition, JNK signaling, ZAK, apoptosis, melanoma, drug toxicity, combination therapy
MeSH terms
Vemurafenib, Animals, Humans, Imidazoles, Indoles, Mice, Hairless, Oximes, Sulfonamides, Signal Transduction, Apoptosis, Proto-Oncogene Proteins B-raf, MAP Kinase Kinase 4, Mice

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