DISCUSSION

This case shows the opposing effects of RAF inhibitors and EGFR and MEK inhibitors on skin and the importance of RAF inhibitor dose-intensity for clinical efficacy and for offsetting toxicity in combination regimens with other ERK pathway inhibitors. As the dose of dabrafenib was reduced, skin toxicity resulting from the EGFR and MEK inhibitors became more pronounced, and when the dabrafenib dose was raised, the toxicity improved, confirming that dabrafenib was modulating skin toxicity resulting from the EGFR and MEK inhibitors. Therefore, although counterintuitive, skin toxicity decreased when the dose of dabrafenib was ultimately increased after failure of maximal supportive care. Differences in RAF signaling underlie the differing effects of RAF inhibitors seen in normal and tumor tissues; in normal tissues, RAF signals as homo-and heterodimers activated by RAS, whereas BRAF V600 mutants, which lead to high ERK activation and feedback suppression of upstream signaling and RAS, signal uniquely as constitutively activated monomers. At clinically achievable doses, RAF inhibitors bind to one site in RAF. In BRAF V600–mutant tumors, this leads to suppression of activated monomers, and in tissues with wild-type RAF kinases (functioning as dimers), this leads to transactivation of RAF dimers. 12, 13 Thus, clinical efficacy and the modulation of toxicity in combination regimens are linked; inhibition of BRAF V600E monomers and paradoxical activation of ERK occur at the same doses. The absence of clinically appreciable opposing effects to EGFR or MEK inhibitors in normal tissues, as occurred in this case, thus suggests inadequate occupation of the first site of RAF dimers in normal tissues as well as of BRAF V600E monomers. 14