MITF Modulates Therapeutic Resistance through EGFR Signaling
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), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (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..
Medienart: |
Artikel |
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Erscheinungsjahr: |
2015 |
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Erschienen: |
2015 |
Enthalten in: |
Zur Gesamtaufnahme - volume:135 |
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Enthalten in: |
The journal of investigative dermatology - 135(2015), 7, Seite 1863-1872 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Ji, Zhenyu [VerfasserIn] |
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Links: |
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RVK: |
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doi: |
10.1038/jid.2015.105 |
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funding: |
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PPN (Katalog-ID): |
OLC1964636698 |
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520 | |a 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), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (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. | ||
650 | 4 | |a Cell Proliferation - genetics | |
650 | 4 | |a Tumor Cells, Cultured - drug effects | |
650 | 4 | |a Melanoma - genetics | |
650 | 4 | |a Sulfonamides - pharmacology | |
650 | 4 | |a Microphthalmia-Associated Transcription Factor - genetics | |
650 | 4 | |a Microphthalmia-Associated Transcription Factor - drug effects | |
650 | 4 | |a Receptor, Epidermal Growth Factor - metabolism | |
650 | 4 | |a Cell Proliferation - drug effects | |
650 | 4 | |a Proto-Oncogene Proteins B-raf - drug effects | |
650 | 4 | |a Melanoma - drug therapy | |
650 | 4 | |a Molecular Targeted Therapy - methods | |
650 | 4 | |a Drug Resistance, Neoplasm - genetics | |
650 | 4 | |a Receptor, Epidermal Growth Factor - drug effects | |
650 | 4 | |a Proto-Oncogene Proteins B-raf - genetics | |
650 | 4 | |a Indoles - pharmacology | |
700 | 1 | |a Erin Chen, Yiyin |4 oth | |
700 | 1 | |a Kumar, Raj |4 oth | |
700 | 1 | |a Taylor, Michael |4 oth | |
700 | 1 | |a Jenny Njauw, Ching-Ni |4 oth | |
700 | 1 | |a Miao, Benchun |4 oth | |
700 | 1 | |a Frederick, Dennie T |4 oth | |
700 | 1 | |a Wargo, Jennifer A |4 oth | |
700 | 1 | |a Flaherty, Keith T |4 oth | |
700 | 1 | |a Jönsson, Göran |4 oth | |
700 | 1 | |a Tsao, Hensin |4 oth | |
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856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/25789707 |
856 | 4 | 2 | |u http://lup.lub.lu.se/record/5258062 |
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