BRAF and melanoma: Within two weeks of exposure to BRAF/MEK inhibitor therapy, in vitro studies suggest that tumor cells paradoxically downregulate melanoma differentiation antigens, with apparent decreases in T cell recognition.175 Biopsies from patients treated with BRAF inhibitors show that both PD-1 and TIM-3, markers of immune exhaustion, are upregulated at the time of tumor progression.176 Given these time-dependent changes in the immune microenvironment, sequencing of drug combinations may be critical.