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

eLife

Kevin B Kim¹  Scarlett B Ferguson²  Karin Ehrenreiter²  Charles H Adelmann³  Vida Chitsazzadeh³  Victor G Prieto⁴  Elsa R Flores⁵  Sandra S Ojeda⁶  Manuela Baccarini⁶  Deepavali Chakravarti⁶  David W Dwyer⁶  Marco L Leung⁶  Monica Restrepo⁶  Harina Vin⁶  Grace Ching⁶  Kristen N Richards⁶  Larissa R Stewart⁶  Lili Du⁶  Kevin N Dalby⁷  Stephen E Ullrich⁸  Rosamaria Ruggieri⁹  Kenneth Y Tsai^1,10  Jonathan L Curry^1,10  Madeleine Duvic^1,11  Ana M Ciurea^1,11 

[1] Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States;Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States;Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Manhasset, United States;Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States;Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, United States;Graduate School of Biomedical Sciences at Houston, University of Texas, Houston, United States;Max F Perutz Laboratories, Vienna, Austria;

关键词: protein kinase;    cancer;    apoptosis;    melanoma;    squamous cell carcinoma;    targeted therapy;   

DOI  :  10.7554/eLife.00969

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown