Discontinuous Vemurafenib Dosing Delays Resistance

Targeted inhibition of BRAF with vemurafenib leads to tumor regression and prolonged survival in many patients with BRAF-mutant metastatic melanoma, but lethal drug-resistant disease almost invariably emerges. Das Thakur and colleagues recapitulated acquired vemurafenib resistance by continuously treating mice bearing a vemurafenib-naïve, patient-derived BRAF-mutant melanoma with vemurafenib until drug resistance developed. Surprisingly, cell lines derived from the drug-resistant tumor could not be established in the absence of vemurafenib. Furthermore, withdrawal of vemurafenib from established cell lines resulted in changes in cell morphology and decreased proliferation caused by elevated ERK signaling, suggesting that the vemurafenib-resistant melanoma cells had become dependent on vemurafenib-mediated modulation of ERK signaling levels. Consistent with these findings, cessation of vemurafenib treatment in mice carrying vemurafenib-resistant melanomas led to tumor regression within 10 days, although tumors eventually resumed growing. These results suggested that intermittent dosing of vemurafenib might create an unfavorable environment for drug-resistant cells and delay the onset of lethal drug resistance. To test this hypothesis, mice bearing primary human melanoma xenografts were given vemurafenib daily on either a continuous or intermittent (4 weeks on, 2 weeks off) schedule. Mice receiving continuous vemurafenib developed lethal drug-resistant disease with 100 days, whereas none of the mice on the intermittent dosing schedule developed resistant disease after 200 days of treatment. These findings indicate that continuous vemurafenib treatment selects for drug-resistant cells but that a discontinuous dosing schedule may select against drug-resistant cells and prolong the responses to vemurafenib therapy. Further studies are warranted to determine whether such altered vemurafenib dosing will be beneficial in patients with BRAF-mutant melanoma and if these observations are applicable to other targeted therapies.

Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013;494:251–5.

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