MITF Modulates Therapeutic Resistance through EGFR Signaling.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Dermatologi och venereologi
Originalspråkengelska
Sidor (från-till)1863-1872
TidskriftJournal of Investigative Dermatology
Volym135
Utgivningsnummer7
StatusPublished - 2015
PublikationskategoriForskning
Peer review utfördJa