Abstract
It is well known that specific signal transduction inhibitors rarely suffice as anti-cancer agents. In most cases, tumors possess primary drug resistance due to their inherent heterogeneity, or acquire drug resistance due to genomic instability and acquisition of mutations. Here we expand our previous study of the novel compound, NT157, and show that it acts as a dual-targeting agent that invokes the blockage of two signal transduction pathways that are central to the development and maintenance of multiple human cancers. We show that NT157 targets not only IGF1R-IRS1/2, as previously reported, but also the Stat3 signaling pathway and demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Levitzki A, Klein S . Signal transduction therapy of cancer. Mol Aspects Med 2010; 31: 287–329.
Levitzki A . Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu Rev Pharmacol Toxicol 2013; 53: 161–185.
Ward HW . Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1973; 1: 13–14.
Druker BJ . Translation of the Philadelphia chromosome into therapy for CML. Blood [Internet]. American Society of Hematology 2008; 112: 4808–4817.
Levitzki A, Mishani E . Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem 2006; 75: 93–109.
Dillman RO . Monoclonal antibodies in the treatment of cancer. Crit Rev Oncol Hematol 1984; 1: 357–385.
Oldham RK . Monoclonal antibodies in cancer therapy. J Clin Oncol 1983; 1: 582–590.
Weinstein IB . Cancer. addiction to oncogenes–the Achilles heal of cancer. Science 2002; 297: 63–64.
Daub H, Specht K, Ullrich A . Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 2004; 3: 1001–1010.
Xia W, Mullin RJ, Keith BR, Liu L-H, Ma H, Rusnak DW et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002; 21: 6255–6263.
Maira S-M, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851–1863.
Darnell JE Jr . STATs and gene regulation. Science 1997; 277: 1630–1635.
Kortylewski M, Jove R, Yu H . Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 2005; 24: 315–327.
Page BDG, Ball DP, Gunning PT . Signal transducer and activator of transcription 3 inhibitors: a patent review. Expert Opin Ther Pat 2011; 21: 65–83.
Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14: 736–746.
Reuveni H, Flashner-Abramson E, Steiner L, Makedonski K, Song R, Shir A et al. Therapeutic destruction of insulin receptor substrates for cancer treatment. Cancer Res 2013; 73: 4383–4394.
Ibuki N, Ghaffari M, Reuveni H, Pandey M, Fazli L, Azuma H et al. The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer. Mol Cancer Ther 2014; 13: 2827–2839.
Schust J, Sperl B, Hollis A, Mayer TU, Berg T . Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 2006; 13: 1235–1242.
Stivarou T, Patsavoudi E . Extracellular molecules involved in cancer cell invasion. Cancers 2015; 7: 238–265.
Pollard JW . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–78.
Qualls J, Neale G, Haverkamp J, Kratochvill F, Smith A, Balouzian L et al. MyD88 and Stat3 signaling are fundamental to tumor associated macrophage function. J Immunol 2012; 188: 34.
Mano Y, Aishima S, Fujita N, Tanaka Y, Kubo Y, Motomura T et al. Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. Pathobiology 2013; 80: 146–154.
Chong CR, Jänne PA . The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med.; 2013; 19: 1389–1400.
Liu F, Cao J, Wu J, Sullivan K, Shen J, Ryu B et al. Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. J Invest Dermatol 2013; 133: 2041–2049.
Li L, Price JE, Fan D, Zhang RD, Bucana CD, Fidler IJ . Correlation of growth capacity of human tumor cells in hard agarose with their in vivo proliferative capacity at specific metastatic sites. J Natl Cancer Inst 1989; 81: 1406–1412.
Acknowledgements
We thank Professor Martin Myers (UMMS) for the Jak2 expression plasmids and Professor Scott Weed (WVU) for the GFP-Src expression plasmids. We thank Professor Ruth Halaban (Yale University) and Yale SPORE in Skin Cancer for providing us with the patient-derived melanoma cells (YUMAC and YUSIK), and Dr Michal Lotem (Hadassah Hospital) for providing us the patient-derived melanoma cells (M571 and M2068). We acknowledge Dr Salim Joubran from our laboratory who was instrumental in the chemistry of NT157. This study was supported by an ERC Advanced Grant (No. 249898) to AL by the NIH Skin Cancer SPORE p50 (No. CA093459), by four grants from the Office of the Chief Scientist in the Ministry of Industry, Trade and Labor of Israel to NovoTyr (HR, 2005–2012) and by Algen Biopharmaceuticals Ltd.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Flashner-Abramson, E., Klein, S., Mullin, G. et al. Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling. Oncogene 35, 2675–2680 (2016). https://doi.org/10.1038/onc.2015.229
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2015.229
This article is cited by
-
NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells
Scientific Reports (2022)
-
NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia
Investigational New Drugs (2021)
-
NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells
Signal Transduction and Targeted Therapy (2020)
-
Dietary compounds and cutaneous malignant melanoma: recent advances from a biological perspective
Nutrition & Metabolism (2019)
-
An in-silico study examining the induction of apoptosis by Cryptotanshinone in metastatic melanoma cell lines
BMC Cancer (2018)