title: 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), 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.
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Zhenyu
authors: Z
authors: Ji
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Yiyin
authors: Y
authors: Erin Chen
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Raj
authors: R
authors: Kumar
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Michael
authors: M
authors: Taylor
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Ching-Ni
authors: CN
authors: Jenny Njauw
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Benchun
authors: B
authors: Miao
authors: MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Dennie T
authors: DT
authors: Frederick
authors: Surgical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Jennifer A
authors: JA
authors: Wargo
authors: MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors: Göran
authors: G
authors: Jönsson
authors: Wellman Center for Photomedicine/Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address: htsao@mgh.harvard.edu.
authors: Hensin
authors: H
authors: Tsao
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D051739:Microphthalmia-Associated Transcription Factor / Q000187:drug effects* / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects / Q000235:genetics; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012878:Skin Neoplasms; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077484:Vemurafenib; D000096142:Cutaneous Malignant Melanoma
chemical_list: D007211:Indoles; D051739:Microphthalmia-Associated Transcription Factor; D013449:Sulfonamides; D000077484:Vemurafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf