Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4


  1. 1

    Levitzki A, Klein S . Signal transduction therapy of cancer. Mol Aspects Med 2010; 31: 287–329.

    CAS  Article  Google Scholar 

  2. 2

    Levitzki A . Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu Rev Pharmacol Toxicol 2013; 53: 161–185.

    CAS  Article  Google Scholar 

  3. 3

    Ward HW . Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1973; 1: 13–14.

    CAS  Article  Google Scholar 

  4. 4

    Druker BJ . Translation of the Philadelphia chromosome into therapy for CML. Blood [Internet]. American Society of Hematology 2008; 112: 4808–4817.

    CAS  Google Scholar 

  5. 5

    Levitzki A, Mishani E . Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem 2006; 75: 93–109.

    CAS  Article  Google Scholar 

  6. 6

    Dillman RO . Monoclonal antibodies in the treatment of cancer. Crit Rev Oncol Hematol 1984; 1: 357–385.

    CAS  Article  Google Scholar 

  7. 7

    Oldham RK . Monoclonal antibodies in cancer therapy. J Clin Oncol 1983; 1: 582–590.

    CAS  Article  Google Scholar 

  8. 8

    Weinstein IB . Cancer. addiction to oncogenes–the Achilles heal of cancer. Science 2002; 297: 63–64.

    CAS  Article  Google Scholar 

  9. 9

    Daub H, Specht K, Ullrich A . Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 2004; 3: 1001–1010.

    CAS  Article  Google Scholar 

  10. 10

    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.

    CAS  Article  Google Scholar 

  11. 11

    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.

    CAS  Article  Google Scholar 

  12. 12

    Darnell JE Jr . STATs and gene regulation. Science 1997; 277: 1630–1635.

    CAS  Article  Google Scholar 

  13. 13

    Kortylewski M, Jove R, Yu H . Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 2005; 24: 315–327.

    CAS  Article  Google Scholar 

  14. 14

    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.

    CAS  Article  Google Scholar 

  15. 15

    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.

    CAS  Article  Google Scholar 

  16. 16

    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.

    CAS  Article  Google Scholar 

  17. 17

    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.

    CAS  Article  Google Scholar 

  18. 18

    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.

    CAS  Article  Google Scholar 

  19. 19

    Stivarou T, Patsavoudi E . Extracellular molecules involved in cancer cell invasion. Cancers 2015; 7: 238–265.

    CAS  Article  Google Scholar 

  20. 20

    Pollard JW . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–78.

    CAS  Article  Google Scholar 

  21. 21

    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.

    Google Scholar 

  22. 22

    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.

    CAS  Article  Google Scholar 

  23. 23

    Chong CR, Jänne PA . The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med.; 2013; 19: 1389–1400.

    CAS  Article  Google Scholar 

  24. 24

    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.

    CAS  Article  Google Scholar 

  25. 25

    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.

    CAS  Article  Google Scholar 

Download references


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



Corresponding authors

Correspondence to H Reuveni or A Levitzki.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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).

Download citation

Further reading