eLife (Nov 2013)
BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling
- Harina Vin,
- Sandra S Ojeda,
- Grace Ching,
- Marco L Leung,
- Vida Chitsazzadeh,
- David W Dwyer,
- Charles H Adelmann,
- Monica Restrepo,
- Kristen N Richards,
- Larissa R Stewart,
- Lili Du,
- Scarlett B Ferguson,
- Deepavali Chakravarti,
- Karin Ehrenreiter,
- Manuela Baccarini,
- Rosamaria Ruggieri,
- Jonathan L Curry,
- Kevin B Kim,
- Ana M Ciurea,
- Madeleine Duvic,
- Victor G Prieto,
- Stephen E Ullrich,
- Kevin N Dalby,
- Elsa R Flores,
- Kenneth Y Tsai
Affiliations
- Harina Vin
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Sandra S Ojeda
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Grace Ching
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Marco L Leung
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States
- Vida Chitsazzadeh
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States
- David W Dwyer
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Charles H Adelmann
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Monica Restrepo
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Kristen N Richards
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States
- Larissa R Stewart
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States
- Lili Du
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States
- Scarlett B Ferguson
- Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, United States
- Deepavali Chakravarti
- Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States; Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, United States
- Karin Ehrenreiter
- Max F Perutz Laboratories, Vienna, Austria
- Manuela Baccarini
- Max F Perutz Laboratories, Vienna, Austria
- Rosamaria Ruggieri
- Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Manhasset, United States
- Jonathan L Curry
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
- Kevin B Kim
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States
- Ana M Ciurea
- Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States
- Madeleine Duvic
- Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States; Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States
- Victor G Prieto
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
- Stephen E Ullrich
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States
- Kevin N Dalby
- Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, United States
- Elsa R Flores
- Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States; Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, United States
- Kenneth Y Tsai
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States; Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States
- DOI
- https://doi.org/10.7554/eLife.00969
- Journal volume & issue
-
Vol. 2
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.
Keywords
