MITF Modulates Therapeutic Resistance through EGFR Signaling.

Research output: Contribution to journalArticle

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.Journal of Investigative Dermatology accepted article preview online, 19 March 2015. doi:10.1038/jid.2015.105.

Details

Authors
  • Zhenyu Ji
  • Yiyin Erin Chen
  • Raj Kumar
  • Michael Taylor
  • Ching-Ni Jenny Njauw
  • Benchun Miao
  • Dennie T Frederick
  • Jennifer A Wargo
  • Keith T Flaherty
  • Göran B Jönsson
  • Hensin Tsao
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Dermatology and Venereal Diseases
Original languageEnglish
Pages (from-to)1863-1872
JournalJournal of Investigative Dermatology
Volume135
Issue number7
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes