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Molecular Cancer
Published in: Molecular Cancer 1/2012

Open Access 01-12-2012 | Research

Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines

Authors: Erika von Euw, Mohammad Atefi, Narsis Attar, Connie Chu, Sybil Zachariah, Barry L Burgess, Stephen Mok, Charles Ng, Deborah JL Wong, Bartosz Chmielowski, David I Lichter, Richard C Koya, Tara A McCannel, Elena Izmailova, Antoni Ribas

Published in: Molecular Cancer | Issue 1/2012

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Abstract

Background

TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.

Methods

The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733.

Results

Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAF V600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRAS Q61L mutant and GNAQ mutant cell lines than in BRAF V600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays.

Conclusions

The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.
Appendix
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Literature
1.
Padua RA, Barrass N, Currie GA: A novel transforming gene in a human malignant melanoma cell line. Nature. 1984, 311: 671-673. 10.1038/311671a0CrossRefPubMed
2.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766CrossRefPubMed
3.
Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE: Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005, 353: 2135-2147. 10.1056/NEJMoa050092CrossRefPubMed
4.
Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, Simpson EM, Barsh GS, Bastian BC: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009, 457: 599-602. 10.1038/nature07586PubMedCentralCrossRefPubMed
5.
Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N: Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010, 363: 2191-2199. 10.1056/NEJMoa1000584PubMedCentralCrossRefPubMed
6.
Gray-Schopfer V, Wellbrock C, Marais R: Melanoma biology and new targeted therapy. Nature. 2007, 445: 851-857. 10.1038/nature05661CrossRefPubMed
7.
Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I: BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006, 439: 358-362. 10.1038/nature04304PubMedCentralCrossRefPubMed
8.
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G: Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010, 467: 596-599. 10.1038/nature09454PubMedCentralCrossRefPubMed
9.
Sondergaard JN, Nazarian R, Wang Q, Guo D, Hsueh T, Mok S, Sazegar H, Macconaill LE, Barretina JG, Kehoe SM: Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific raf inhibitor PLX4032. J Transl Med. 2010, 8: 39- 10.1186/1479-5876-8-39PubMedCentralCrossRefPubMed
10.
Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A: The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010, 107: 14903-14908. 10.1073/pnas.1008990107PubMedCentralCrossRefPubMed
11.
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010, 363: 809-819. 10.1056/NEJMoa1002011PubMedCentralCrossRefPubMed
12.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011, 364: 2507-2516. 10.1056/NEJMoa1103782PubMedCentralCrossRefPubMed
13.
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012, 366: 707-714. 10.1056/NEJMoa1112302PubMedCentralCrossRefPubMed
14.
Lin WM, Baker AC, Beroukhim R, Winckler W, Feng W, Marmion JM, Laine E, Greulich H, Tseng H, Gates C: Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 2008, 68: 664-673. 10.1158/0008-5472.CAN-07-2615CrossRefPubMed
15.
Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM: Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008, 40: 600-608. 10.1038/ng.115PubMedCentralCrossRefPubMed
16.
Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N: (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009, 106: 4519-4524. 10.1073/pnas.0900780106PubMedCentralCrossRefPubMed
17.
Zuidervaart W, van Nieuwpoort F, Stark M, Dijkman R, Packer L, Borgstein AM, Pavey S, van der Velden P, Out C, Jager MJ: Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer. 2005, 92: 2032-2038. 10.1038/sj.bjc.6602598PubMedCentralCrossRefPubMed
18.
Weber A, Hengge UR, Urbanik D, Markwart A, Mirmohammadsaegh A, Reichel MB, Wittekind C, Wiedemann P, Tannapfel A: Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Investig. 2003, 83: 1771-1776. 10.1097/01.LAB.0000101732.89463.29CrossRefPubMed
19.
Dong Q, Dougan DR, Gong X, Halkowycz P, Jin B, Kanouni T, O'Connell SM, Scorah N, Shi L, Wallace MB, Zhou F: Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett. 2011, 21: 1315-1319. 10.1016/j.bmcl.2011.01.071CrossRefPubMed
20.
O’ Connell S, Tsuchiya S, Shi L, Fabrey R, Zhang L, Dong Q, Hori A, Vincent P: BRAF is not the only predictor of sensitivity in vitro and in vivo for TAK-733, a selective potent inhibitor of MEK1/2. Proc Am Assoc Canc Res. 2010, Abstract #2523
21.
Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB: MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009, 106: 20411-20416. 10.1073/pnas.0905833106PubMedCentralCrossRefPubMed
22.
Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B: Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One. 2011, 6: e28973- 10.1371/journal.pone.0028973PubMedCentralCrossRefPubMed
23.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012, 483: 100-103. 10.1038/nature10868CrossRefPubMed
24.
Shi H, Kong X, Ribas A, Lo RS: Combinatorial Treatments That Overcome PDGFR{beta}-Driven Resistance of Melanoma Cells to V600EB-RAF Inhibition. Cancer Res. 2011, 71: 5067-5074. 10.1158/0008-5472.CAN-11-0140PubMedCentralCrossRefPubMed
25.
Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, Dummer R: Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012, 18: 555-567. 10.1158/1078-0432.CCR-11-1491CrossRef
26.
Infante JR, Fecher LA, Nallapareddy S, Gordon MS, Flaherty KT, Cox DS, DeMarini DJ, Morris SR, Burris HA, Messersmith WA: Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol. 2010, Abstract 2503
27.
Kefford R, Arkenau H, Brown MP, Millward M, Infante JR, Long GV, Ouellet D, Curtis M, Lebowitz PF, Falchokk GS: Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol. 2010, 28: 611s-10.1200/JCO.2010.30.0418. 10.1200/JCO.2010.30.0418CrossRef
28.
Hall-Jackson CA, Eyers PA, Cohen P, Goedert M, Boyle FT, Hewitt N, Plant H, Hedge P: Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol. 1999, 6: 559-568. 10.1016/S1074-5521(99)80088-XCrossRefPubMed
29.
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012, 366: 207-215. 10.1056/NEJMoa1105358PubMedCentralCrossRefPubMed
30.
MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C: Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009, 4: e7887- 10.1371/journal.pone.0007887PubMedCentralCrossRefPubMed
31.
Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, Czernin J, Shyy JY, Watson AD, Phelps M: The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci U S A. 2009, 106: 12932-12937. 10.1073/pnas.0906606106PubMedCentralCrossRefPubMed
Metadata
Title
Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines
Authors
Erika von Euw
Mohammad Atefi
Narsis Attar
Connie Chu
Sybil Zachariah
Barry L Burgess
Stephen Mok
Charles Ng
Deborah JL Wong
Bartosz Chmielowski
David I Lichter
Richard C Koya
Tara A McCannel
Elena Izmailova
Antoni Ribas
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2012
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-11-22

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