Targeting MITF in the tolerance-phase

6 years ago melanoma was an untreatable cancer without an effective therapy beyond surgical excision, but today immune checkpoint-and MAP-kinase (MAPK)-pathway targeting therapies have significantly improved patient survival. Nevertheless, the plethora of reports on the inevitable development of resistance in the majority of patients treated with BRAF and MEK inhibitors has greatly distracted from the remarkable initial responses these drugs produce in patients with BRAF mutant melanoma. In an attempt to better understand the onset of resistance to MAPK-targeting inhibitors in melanoma patients, we have focused on the initial response phase, when tumours shrink because melanoma cell survival is strictly dependent on MAPK-signalling. We identified an early cell autonomous-driven non-mutational 'tolerance phase', in which melanoma cells in order to adapt to the loss of the vital MAPK signals rewire their signalling and enhance expression of the MIcrophthalmia Transcription Factor (MITF), one of the major drivers of melanoma cell identity [1]. In line with our previous findings [2], we could demonstrate that by up-regulating MITF expression melanoma cells can withstand the MAPK-inhibitor induced toxicity even before the establishment of mutational acquired resistance. This suggested that targeting MITF during the 'tolerance phase' could sensitize melanoma cells to MAPK-pathway inhibitors, thereby providing a window of opportunity for therapeutic intervention that would allow extending the efficacy of these drugs. Indeed, the HIV-protease inhibitor nelfinavir, which we identified as a potent down-regulator of MITF expression, profoundly increased the cytotoxicity of MAPK-inhibitors and reduced the development of resistance [1]. Although these pre-clinical results are encouraging, there are several questions that require further exploration. One of the potential concerns suggested in light of our findings is the possibility that MITF down-regulation could turn melanoma cells into so-called 'MITF low cells', melanoma cell sub-populations found in ~20% of melanomas that are no longer driven by MITF but rather display a gene expression signature governed by receptor tyrosine kinase (such as AXL, EGFR, ERBB3), WNT5A or NFkB signalling [3-5]. Importantly, these MITF low / AXL high cells are greatly resistant to MAPK-inhibitors [3-5], and ~50% of melanomas identified in patients relapsed on MAPK-inhibitor treatment display reduced MITF expression possibly linked to the AXL high-signature. While this suggest a selection for reduced MITF expression in half the melanomas that progress on MAPK-inhibitor treatment alone, it is not known whether this frequency would change in patients that would escape a nelfinavir/ MAPK-inhibitor combination therapy, where during treatment, the MITF down-regulated cells …