Targeting BRD/BET proteins inhibits adaptive kinome upregulation and enhances the effects of BRAF/MEK inhibitors in melanoma.

Publication date: Jan 14, 2020

BRAF-mutant melanoma patients respond to BRAF inhibitors and MEK inhibitors (BRAFi/MEKi), but drug-tolerant cells persist, which may seed disease progression. Adaptive activation of receptor tyrosine kinases (RTKs) has been associated with melanoma cell drug tolerance following targeted therapy. While co-targeting individual RTKs can enhance the efficacy of BRAFi/MEKi effects, it remains unclear how to broadly target multiple RTKs to achieve more durable tumour growth inhibition.

The blockage of adaptive RTK responses by the new BET inhibitor (BETi), PLX51107, was measured by RPPA and Western blot. Melanoma growth was evaluated in vitro by colony assay and EdU staining, as well as in skin reconstructs, xenografts and PDX models following BRAFi, MEKi and/or PLX51107 treatment.

Treatment with PLX51107 limited BRAFi/MEKi upregulation of ErbB3 and PDGFR-? expression levels. Similar effects were observed following BRD2/4 depletion. In stage III melanoma patients, expression of BRD2/4 was strongly correlated with ErbB3. PLX51107 enhanced the effects of BRAFi/MEKi on inhibiting melanoma growth in vitro, in human skin reconstructs and in xenografts in vivo. Continuous triple drug combination treatment resulted in significant weight loss in mice, but intermittent BETi combined with continuous BRAFi/MEKi treatment was tolerable and improved durable tumour inhibition outcomes.

Together, our data suggest that intermittent inhibition of BET proteins may improve the duration of responses following BRAFi/MEKi treatment in BRAF-mutant melanoma.

Tiago, M., Capparelli, C., Erkes, D.A., Purwin, T.J., Heilman, S.A., Berger, A.C., Davies, M.A., and Aplin, A.E. Targeting BRD/BET proteins inhibits adaptive kinome upregulation and enhances the effects of BRAF/MEK inhibitors in melanoma. 25454. 2020 Br J Cancer.

Concepts Keywords
Assay Tyrosine kinase receptors
BET Antineoplastic drugs
BRAF Cancer
Colony Medicine
Drug Tolerance Clinical medicine
MEK Melanoma
Melanoma Enzymes
Mice III melanoma
Mutant Tumour
PDGFR Melanoma
Staining MEK inhibitor
Targeted Therapy ERBB3
Tumour BRAF
Tyrosine Targeted therapy
Weight Loss
Western Blot


Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
disease MESH disease progression
drug DRUGBANK L-Tyrosine
disease MESH drug tolerance
disease MESH multiple
disease MESH growth
drug DRUGBANK Pralatrexate
disease MESH weight loss


Original Article

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