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MITF Modulates Therapeutic Resistance through EGFR Signaling.

Ji, Zhenyu ; Erin Chen, Yiyin ; Kumar, Raj ; Taylor, Michael ; Jenny Njauw, Ching-Ni ; Miao, Benchun ; Frederick, Dennie T ; Wargo, Jennifer A ; Flaherty, Keith T and Jönsson, Göran B LU , et al. (2015) In Journal of Investigative Dermatology 135(7). p.1863-1872
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,... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Investigative Dermatology
volume
135
issue
7
pages
1863 - 1872
publisher
Elsevier
external identifiers
  • pmid:25789707
  • wos:000356180100025
  • scopus:84931050367
  • pmid:25789707
ISSN
1523-1747
DOI
10.1038/jid.2015.105
language
English
LU publication?
yes
id
153b40d7-0b28-4c7e-813b-0dbca621ac6a (old id 5258062)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25789707?dopt=Abstract
date added to LUP
2016-04-01 10:45:49
date last changed
2025-04-04 14:10:26
@article{153b40d7-0b28-4c7e-813b-0dbca621ac6a,
  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.}},
  author       = {{Ji, Zhenyu and Erin Chen, Yiyin and Kumar, Raj and Taylor, Michael and Jenny Njauw, Ching-Ni and Miao, Benchun and Frederick, Dennie T and Wargo, Jennifer A and Flaherty, Keith T and Jönsson, Göran B and Tsao, Hensin}},
  issn         = {{1523-1747}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1863--1872}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Investigative Dermatology}},
  title        = {{MITF Modulates Therapeutic Resistance through EGFR Signaling.}},
  url          = {{http://dx.doi.org/10.1038/jid.2015.105}},
  doi          = {{10.1038/jid.2015.105}},
  volume       = {{135}},
  year         = {{2015}},
}