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
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States.
Elife. 2013 Nov 5;2:e00969. doi: 10.7554/eLife.00969.
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. DOI: http://dx.doi.org/10.7554/eLife.00969.001.
维莫非尼和达拉非尼可选择性抑制v-Raf鼠肉瘤病毒癌基因同源物B1（BRAF）激酶，从而在黑色素瘤治疗中实现高缓解率并延长生存期。接受维莫非尼治疗的患者中约有22%在治疗期间发生皮肤鳞状细胞癌（cSCC）。对此现象的普遍解释是药物诱导的反常ERK激活，导致细胞过度增殖。在此我们展示了维莫非尼/PLX4720通过抑制c-Jun氨基末端激酶（JNK）上游的多种脱靶激酶（主要是ZAK）来抑制细胞凋亡这一意外的新效应。JNK信号在多种情况下受到抑制，包括在接受维莫非尼治疗患者的cSCC中以及在小鼠体内。一种无法被抑制的突变型ZAK的表达可逆转对JNK激活和细胞凋亡的抑制。我们的结果表明，抑制JNK依赖性细胞凋亡是一种与反常ERK激活协同作用以诱导cSCC的重要独立机制，这对于理解与BRAF抑制剂相关的毒性及其在联合治疗中的应用具有广泛意义。DOI：http://dx.doi.org/10.7554/eLife.00969.001 。
