Top

Published in:

01-06-2017 | Original Article

MITF suppression by CH5552074 inhibits cell growth in melanoma cells

Authors: Satoshi Aida, Yukiko Sonobe, Munehiro Yuhki, Kiyoaki Sakata, Toshihiko Fujii, Hiroshi Sakamoto, Takakazu Mizuno

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2017

Abstract

Purpose

Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.

Methods

We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.

Results

We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.

Conclusions

These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

Available only for authorised users

Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516CrossRefPubMedPubMedCentral

Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703CrossRefPubMedPubMedCentral

Larkin J, Ascierto PA, Dréno B et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20):1867–1876CrossRefPubMed

Johannessen CM, Johnson LA, Piccioni F et al (2013) A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504(7478):138–142CrossRefPubMedPubMedCentral

Van Allen EM, Wagle N, Sucker A et al (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4(1):94–109CrossRefPubMed

Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723CrossRefPubMedPubMedCentral

Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (Anti–PD-1) in melanoma. N Engl J Med 369(2):134–144CrossRefPubMedPubMedCentral

Robert C, Ribas A, Wolchok JD et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384(9948):1109–1117CrossRefPubMed

Postow MA, Chesney J, Pavlick AC et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372(21):2006–2017CrossRefPubMed

10.

King R, Googe PB, Weilbaecher KN et al (2001) Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors. The American journal of surgical pathology 25(1):51–57CrossRefPubMed

11.

Levy C, Khaled M, Fisher DE (2006) MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 12(9):406–414CrossRefPubMed

12.

Wellbrock C, Rana S, Paterson H et al (2008) Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One 3(7):e2734CrossRefPubMedPubMedCentral

13.

Garraway LA, Widlund HR, Rubin MA et al (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436(7047):117–122CrossRefPubMed

14.

Mizuno H, Nakanishi Y, Ishii N et al (2009) A signature-based method for indexing cell cycle phase distribution from microarray profiles. BMC Genom 10(1):1–10CrossRef

15.

Krämer A, Green J, Pollard J et al (2014) Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30(4):523–530CrossRefPubMed

16.

Nakanishi Y, Mizuno H, Sase H et al (2015) ERK signal suppression and sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor. Mol Cancer Ther 14(12):2831–2839CrossRefPubMed

17.

Miller AJ, Du J, Rowan S et al (2004) Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Cancer Res 64(2):509–516CrossRefPubMed

18.

Du J, Fisher DE (2002) Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF. J Biol Chem 277(1):402–406CrossRefPubMed

19.

Moffat JG, Rudolph J, Bailey D (2014) Phenotypic screening in cancer drug discovery—past, present and future. Nat Rev Drug Discov 13(8):588–602CrossRefPubMed

20.

Yamaguchi T, Yoshida T, Kurachi R et al (2007) Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci 98(11):1809–1816CrossRefPubMed

21.

Smith MP, Ferguson J, Arozarena I et al (2013) Effect of SMURF2 targeting on susceptibility to MEK inhibitors in melanoma. J Natl Cancer Inst 105(1):33–46CrossRefPubMed

22.

Borgdorff V, Rix U, Winter GE et al (2014) A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF. Oncogene 33(19):2531–2539CrossRefPubMed

23.

Yokoyama S, Feige E, Poling LL et al (2008) Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res 21(4):457–463CrossRefPubMedPubMedCentral

24.

Smith Michael P, Brunton H, Rowling Emily J et al (2016) Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29(3):270–284CrossRefPubMedPubMedCentral

25.

Kubic JD, Young KP, Plummer RS et al (2008) Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease. Pigment Cell Melanoma Res 21(6):627–645CrossRefPubMedPubMedCentral

26.

Haq R, Shoag J, Andreu-Perez P et al (2013) Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23(3):302–315CrossRefPubMedPubMedCentral

27.

Gopal YNV, Rizos H, Chen G et al (2014) Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res 74(23):7037–7047CrossRefPubMedPubMedCentral

Title: MITF suppression by CH5552074 inhibits cell growth in melanoma cells
Authors: Satoshi Aida
Yukiko Sonobe
Munehiro Yuhki
Kiyoaki Sakata
Toshihiko Fujii
Hiroshi Sakamoto
Takakazu Mizuno
Publication date: 01-06-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2017
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3317-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2017

UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis

Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study

Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue

Induction chemotherapy followed by concurrent chemoradiotherapy vs. concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a retrospective cohort study

A phase I study of cilengitide and paclitaxel in patients with advanced solid tumors

Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer