MITF Modulates Therapeutic Resistance through EGFR Signaling

Abstract

Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR induced vemurafenib resistance is ligand dependent. We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients’ tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an “autocrine drug resistance loop” is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

“…Second, the invasive program, and not the proliferative program, appears to be the dominant determinant of therapeutic response, since this clearly overrides the negative effect of MITF on both invasiveness and drug response. Interestingly, MITF is known to confer sensitivity to BRAFi via inhibition of EGFR expression (Ji et al 2015). We found that BMI1 expression leads to up-regulation of both EGFR and PDGFR, offering a simple mechanism to counteract the effect of MITF.…”

miR-579-3p controls melanoma progression and resistance to target therapy

“…Recent data strongly correlated loss of MITF expression with drug resistance (46)(47)(48). miR-579-3p is an intronic miR located in intron 11 of the human gene ZFR (Zink-finger recombinase), and it is probably coexpressed with its host gene (49).…”

Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development

“…MITF loss at the transcriptional level occurs in four of seven melanoma cell lines, which have acquired in vitro resistance to the BRAF inhibitor PLX4720 (Muller et al., ). An independent study performed in two independent melanoma cell lines, SKMEL28 and MGH‐CH1, also showed that the emergence of vemurafenib resistance was correlated with MITF loss (Ji et al., ). Furthermore, low MITF levels and innate resistance to BRAFi have also been associated.…”

“…A second example of the impact of MITF loss on RTK activation is illustrated by the link MITF/EGFR. The emergence of vemurafenib resistance in the two melanoma cell lines, SKMEL28 and MGH‐CH1, was correlated with MITF loss, in association with EGFR activation (Ji et al., ). Further exploring this association, the investigatiors demonstrated that MITF suppression increased the expression of heparin‐binding EGF (HB‐EGF) and transforming growth factor‐α, two EGFR ligands.…”