Epigenetic Changes of EGFR Have an Important Role in BRAF Inhibitor–Resistant Cutaneous Melanomas

Wang, Jinhua; Huang, Sharon K.; Marzese, Diego M.; Hsu, Sandy C.; Kawas, Neal P.; Chong, Kelly K.; Long, Georgina V.; Menzies, Alexander M.; Scolyer, Richard A.; Izraely, Sivan; Sagi‐Assif, Orit; Hoon, Dave S.B.

doi:10.1038/jid.2014.418

Cited by 81 publications

(76 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several reports have demonstrated that melanoma cells selected for resistance to BRAF V600E inhibitors, including the clinically utilized small molecule vemurafenib, acquire increased invasion compared to parental counterparts (27, 36, 37). This increase in invasion has been attributed to the loss of MITF (27–29).…”

Section: Resultsmentioning

confidence: 99%

“…It has been recently shown that acquisition of resistance to vemurafenib occurs, at least in part, through suppression of MITF (27–29). Accordingly, vemurafenib-resistant cells often possess a higher invasive potential compared to parental counterparts (27, 36, 37), a feature which may contribute to the enhanced growth of vemurafenib-resistant tumors. Our data argue that inhibition of MITF-GMPR axis plays a pivotal role in the increased invasion of vemurafenib resistant cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

et al. 2016

View full text Add to dashboard Cite

Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells, however little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion. We further demonstrate that the gene for guanosine monophosphate reductase (GMPR) is a direct MITF target, and that the partial repression of GMPR accounts mostly for the above phenotypes in MITF-depleted cells. Reciprocally, transactivation of GMPR is required for MITF-dependent suppression of melanoma cell invasion, tumorigenicity, and lung colonization. Moreover, loss of GMPR accompanies downregulation of MITF in vemurafenib-resistant BRAFV600E-melanoma cells and underlies the increased invasion in these cells. Our data uncover novel mechanisms linking MITF-dependent inhibition of invasion to suppression of guanylate metabolism.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Epigenetic regulation of EGFR expression at its promoter has been recognized in other solid tumors. 30,31 In colorectal cancer cells, for example, dissociation of SP1 and the CREB-binding protein (CBP) from the EGFR promoter leads to its hypoacetylation and transcriptional downregulation. 32 We hypothesized that EGFR silencing during neural differentiation and its aberrant expression in gliomas are at least partly mediated via local epigenetic mechanisms at its proximal promoter, modulating accessibility of transcription factors for regulation of gene expression.…”

Section: Introductionmentioning

confidence: 99%

EGFRpromoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas

Erfani¹,

Tomé-García

Canoll

et al. 2015

Epigenetics

View full text Add to dashboard Cite

Several signaling pathways important for the proliferation and growth of brain cells are pathologically dysregulated in gliomas, including the epidermal growth factor receptor (EGFR). Expression of EGFR is high in neural progenitors during development and in gliomas but decreases significantly in most adult brain regions. Here we show that EGFR expression is maintained in the astrocyte ribbon of the adult human subventricular zone. The transcriptional regulation of EGFR expression is poorly understood. To investigate the role of epigenetics on EGFR regulation in the contexts of neural development and gliomagenesis, we measured levels of DNA methylation and histone H3 modifications at the EGFR promoter in human brain tissues, glioma specimens, and EGFR-expressing neural cells, acutely isolated from their native niche. While DNA was constitutively hypomethylated in non-neoplastic and glioma samples, regardless of their EGFR-expression status, the activating histone modifications H3K27ac and H3K4me3 were enriched only when EGFR is highly expressed (developing germinal matrix and gliomas). Conversely, repressive H3K27me3 marks predominated in adult white matter where EGFR is repressed. Furthermore, the histone methyltransferase core enzyme ASH2L was bound at EGFR in the germinal matrix and in gliomas where levels of H3K4me3 are high, and the histone acetyltransferase P300 was bound in samples with H3K27ac enrichment. Our studies use human cells and tissues undisturbed by cell-culture artifact, and point to an important, locus-specific role for chromatin remodeling in EGFR expression in human neural development that may be dysregulated during gliomagenesis, unraveling potential novel targets for future drug therapy.

show abstract

“…A rapid series of advances have demonstrated both exceptional initial patient response, and ready emergence of therapy-resistant disease. Identified resistance mechanisms include gain-of-function mutations in NRAS (6), MAP2K1 (7, 8) and PIK3CA (9); amplification of COT (10), upregulation of PDGFRβ (6), EGFR (11–13), ERBB3 (14) and IGFR1 (15); and amplification (16) or alternative splice variant expression of BRAF (17). The majority of these resistance mechanisms appear to be a consequence of BRAF(V600)-independent mitogen-activated protein kinase (MAPK) pathway activation.…”

Section: Introductionmentioning

confidence: 99%

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

et al. 2017

Self Cite

View full text Add to dashboard Cite

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.

show abstract

Epigenetic Changes of EGFR Have an Important Role in BRAF Inhibitor–Resistant Cutaneous Melanomas

Cited by 81 publications

References 51 publications

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

EGFRpromoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

Contact Info

Product

Resources

About