TY - JOUR
T1 - Targeting BRD/BET proteins inhibits adaptive kinome upregulation and enhances the effects of BRAF/MEK inhibitors in melanoma
AU - Tiago, Manoela
AU - Capparelli, Claudia
AU - Erkes, Dan A.
AU - Purwin, Timothy J.
AU - Heilman, Shea A.
AU - Berger, Adam C.
AU - Davies, Michael A.
AU - Aplin, Andrew E.
N1 - Funding Information:
Funding information This work was supported by grants from NIH/NCI (R01 CA160495 and R01 CA182635) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to A.E.A., and National Cancer Center Fellowship and the Rochester Melanoma Action Group/Outrun the Sun Melanoma Research Scholar Award to M.T. The Flow Cytometry, Lab Animal, and Meta-Omics shared resources at the SKCC were supported by NIH/NCI Cancer Center Support Grant, P30 CA056036. The RPPA studies were performed at the Functional Proteomics Core Facility at The University of Texas MD Anderson Cancer Center, which is supported by the NIH/NCI Cancer Center Support Grant, P30 CA16672.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - Background: 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. Methods: 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. Results: Treatment with PLX51107 limited BRAFi/MEKi upregulation of ErbB3 and PDGFR-β 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. Conclusions: Together, our data suggest that intermittent inhibition of BET proteins may improve the duration of responses following BRAFi/MEKi treatment in BRAF-mutant melanoma.
AB - Background: 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. Methods: 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. Results: Treatment with PLX51107 limited BRAFi/MEKi upregulation of ErbB3 and PDGFR-β 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. Conclusions: Together, our data suggest that intermittent inhibition of BET proteins may improve the duration of responses following BRAFi/MEKi treatment in BRAF-mutant melanoma.
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U2 - 10.1038/s41416-019-0724-y
DO - 10.1038/s41416-019-0724-y
M3 - Article
C2 - 31932756
AN - SCOPUS:85078608370
SN - 0007-0920
VL - 122
SP - 789
EP - 800
JO - British journal of cancer
JF - British journal of cancer
IS - 6
ER -