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. DOI: http://dx.doi.org/10.7554/eLife.00969.001.
Highlights
Clinical trials have shown that a drug called vemurafenib can be used to treat patients who carry the mutated BRAF genes and go on to develop melanoma, but around one fifth of these patients developed another type of skin cancer called cutaneous squamous cell carcinoma (cSCC)
PLX4720 potently suppresses apoptosis in cSCC, HaCaT cell lines, and normal human epidermal keratinocytes (NHEKs) cells
To test the generality of these effects in cells in which ERK activity is suppressed by BRAFi, we extended our analysis to the BRAFV600E melanoma cells A375 and WM35
Summary
BRAF inhibitors (BRAFi) have revolutionized the treatment of melanoma (Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012; Falchook et al, 2012; Hauschild et al, 2012; Long et al, 2012) Their clinical use is associated with the development of keratinocytic tumors including cSCC Clinical trials have shown that a drug called vemurafenib can be used to treat patients who carry the mutated BRAF genes and go on to develop melanoma, but around one fifth of these patients developed another type of skin cancer called cSCC (cutaneous squamous cell carcinoma)
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