Editors' ChoiceCancer

Melanoma’s triple threat

Sci. Signal.  24 Mar 2015:
Vol. 8, Issue 369, pp. ec70
DOI: 10.1126/scisignal.aab1592

Combination therapy is the favored approach to fight drug-resistant cancer. For BRAF-mutated melanoma, combining a BRAF inhibitor and inhibitors of negative regulators of T cells was attempted to boost the immune response to the cancer; however, a clinical trial was stopped because of liver toxicity. BRAF activates the mitogen-activated protein kinase (MAPK) pathway through the kinase MEK, which activates the kinases ERK1 and ERK2. Hu-Lieskovan et al. found that combining a MEK inhibitor (trametinib) and a BRAF inhibitor (dabrafenib) enhanced the antitumor activity of engineered T cells that were adoptively transferred (ACT immunotherapy) into a mouse model of BRAFV600E-driven melanoma. Unexpectedly, although in culture the cells used for ACT exhibited reduced cytotoxicity and cytokine secretion when exposed to dabrafenib and trametinib, the cytoxicity of the cells in vivo was unimpaired in mice injected with the two drugs. In addition, replacing ACT with an agent that inhibits PD1, a negative regulator of T cells, in the triple therapy produced similar tumor regression as the ACT triple therapy, suggesting that patients with BRAF-mutated melanoma may benefit by combining MEK and BRAF inhibition with various immunotherapies.

S. Hu-Lieskovan, S. Mok, B. Homet Moreno, J. Tsoi, L. Robert, L. Goedert, E. M. Pinheiro, R. C. Koya, T. G. Graeber, B. Comin-Anduix, A. Ribas, Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci. Transl. Med. 7, 279ra41 (2015). [Abstract]