Varlitinib Mediates Its Activity Through Down Regulating MAPK/EGFR Pathway in Oral Cancer

Author(s): Muhammad Usman, Fariha Tanveer, Amber Ilyas, Shamshad Zarina*

Journal Name: Current Proteomics

Volume 17 , Issue 1 , 2020

DOI : 10.2174/1570164616666190516114749

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Abstract:

Background: Oral Squamous Cell Carcinoma (OSCC) is a major sub-type of oral cancer that shares 90% proportion of oral cavity cancers. It is declared as the sixth most frequent cancer among all cancer types throughout the world. Higher morbidity in Asian countries is reported due to frequent use of Smokeless Tobacco (SLT) products besides exposure to other risk factors. Hyperactivation of epidermal growth factor receptors is a molecular event in many solid tumors including oral cancer making them potential therapeutic targets.

Objective: Current study was designed to explore the effect of varlitinib, a pan-HER inhibitor, on oral cancer cell line. We investigated key regulatory genes in downstream pathway in response to drug treatment. Furthermore, we also examined expression profile of these genes in malignant and healthy oral tissue.

Methods: Gene expression pattern in drug treated and untreated cancer cell line along with OSCC tumor samples (n=45) and adjacent normal tissues was studied using real time PCR.

Results: In response to varlitinib treatment, significant suppression of oncogenes (IGF1R, MAPK1, SFN and CDK2) was observed. Interestingly, mRNA expression level of CDKN1A and Akt1 was found to be the opposite of what was expected. In case of malignant tissue, over expression of oncogenes (IGF1R, Akt1, MAPK1, SFN and CDK2) with simultaneous down expression of tumor suppressor genes (Tp53 and CDKN1A) was noted. STRING analysis indicated a strong association among differentially expressed genes suggesting their combined role in carcinogenesis.

Conclusion: In summary, our results indicate that varlitinib can be considered as a potential therapeutic agent in oral cancer due to its antitumor potential.

Keywords: Oral carcinoma, signal transduction, EGFR pathway, SCC-25 OSCC cell lines, Varlitinib, tobacco.

[1]
Leemans, C.R.; Braakhuis, B.J.; Brakenhoff, R.H. The molecular biology of head and neck cancer. Nat. Rev. Cancer, 2011, 11(1), 9-22.
[http://dx.doi.org/10.1038/nrc2982] [PMID: 21160525]
[2]
Peng, C.H.; Liao, C.T.; Peng, S.C.; Cheng, A.; Juang, J.L.; Tsai, C.Y.; Chen, T.S.; Chuang, Y.J.; Tang, C.Y.; Hsieh, W.P.; Yen, T.C. A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One, 2011, 6(8)e23452
[http://dx.doi.org/10.1371/journal.pone.0023452] [PMID: 21853135]
[3]
Boyle, P.; Macfarlane, G.J.; Scully, C. Oral cancer: necessity for prevention strategies. Lancet, 1993, 342(8880), 1129.
[http://dx.doi.org/10.1016/0140-6736(93)92119-E] [PMID: 7901471]
[4]
Hashibe, M.; Brennan, P.; Chuang, S.C.; Boccia, S.; Castellsague, X.; Chen, C.; Curado, M.P.; Dal Maso, L.; Daudt, A.W.; Fabianova, E.; Fernandez, L.; Wünsch-Filho, V.; Franceschi, S.; Hayes, R.B.; Herrero, R.; Kelsey, K.; Koifman, S.; La Vecchia, C.; Lazarus, P.; Levi, F.; Lence, J.J.; Mates, D.; Matos, E.; Menezes, A.; McClean, M.D.; Muscat, J.; Eluf-Neto, J.; Olshan, A.F.; Purdue, M.; Rudnai, P.; Schwartz, S.M.; Smith, E.; Sturgis, E.M.; Szeszenia-Dabrowska, N.; Talamini, R.; Wei, Q.; Winn, D.M.; Shangina, O.; Pilarska, A.; Zhang, Z.F.; Ferro, G.; Berthiller, J.; Boffetta, P. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the international head and neck cancer epidemiology consortium. Cancer Epidemiol. Biomarkers Prev., 2009, 18(2), 541-550.
[http://dx.doi.org/10.1158/1055-9965.EPI-08-0347] [PMID: 19190158]
[5]
Ali, N.S.; Khuwaja, A.K.; Ali, T.; Hameed, R. Smokeless tobacco use among adult patients who visited family practice clinics in Karachi, Pakistan. J. Oral Pathol. Med., 2009, 38(5), 416-421.
[http://dx.doi.org/10.1111/j.1600-0714.2009.00754.x] [PMID: 19434816]
[6]
Sardas, S.; Cimen, B.; Karsli, S.; Yurdun, T.; Donbak, L. Comparison of genotoxic effect between smokeless tobacco (Maras powder) users and cigarette smokers by the alkaline comet assay. Hum. Exp. Toxicol., 2009, 28(4), 214-219.
[http://dx.doi.org/10.1177/0960327108098333] [PMID: 19734273]
[7]
Zheng, W.; Soo, K.C.; Sivanandan, R.; Olivo, M. Detection of neoplasms in the oral cavity by digitized endoscopic imaging of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. Int. J. Oncol., 2002, 21(4), 763-768.
[http://dx.doi.org/10.3892/ijo.21.4.763] [PMID: 12239614]
[8]
Schwartz, G.J.; Mehta, R.H.; Wenig, B.L.; Shaligram, C.; Portugal, L.G. Salvage treatment for recurrent squamous cell carcinoma of the oral cavity. Head Neck, 2000, 22(1), 34-41.
[http://dx.doi.org/10.1002/(SICI)1097-0347(200001)22:1<34: AID-HED6>3.0.CO;2-3] [PMID: 10585603]
[9]
Shah, J.P.; Gil, Z. Current concepts in management of oral cancer-surgery. Oral Oncol., 2009, 45(4-5), 394-401.
[http://dx.doi.org/10.1016/j.oraloncology.2008.05.017] [PMID: 18674952]
[10]
Pignon, J.; Bourhis, J.; Domenge, C.; Designé, L. Group, M.N.C. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet, 2000, 355(9208), 949-955.
[http://dx.doi.org/10.1016/S0140-6736(00)90011-4] [PMID: 10768432]
[11]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 2005, 315(3), 971-979.
[http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463]
[12]
Warnakulasuriya, S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol., 2009, 45(4-5), 309-316.
[http://dx.doi.org/10.1016/j.oraloncology.2008.06.002] [PMID: 18804401]
[13]
Sharafinski, M.E.; Ferris, R.L.; Ferrone, S.; Grandis, J.R. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck, 2010, 32(10), 1412-1421.
[http://dx.doi.org/10.1002/hed.21365] [PMID: 20848399]
[14]
Seshacharyulu, P.; Ponnusamy, M.P.; Haridas, D.; Jain, M.; Ganti, A.K.; Batra, S.K. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets, 2012, 16(1), 15-31.
[http://dx.doi.org/10.1517/14728222.2011.648617] [PMID: 22239438]
[15]
Wieduwilt, M.J.; Moasser, M.M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci., 2008, 65(10), 1566-1584.
[http://dx.doi.org/10.1007/s00018-008-7440-8] [PMID: 18259690]
[16]
Wong, D.T.W.; Todd, R.; Tsuji, T.; Donoff, R.B. Molecular biology of human oral cancer. Crit. Rev. Oral Biol. Med., 1996, 7(4), 319-328.
[http://dx.doi.org/10.1177/10454411960070040201] [PMID: 8986394]
[17]
Mendelsohn, J. The epidermal growth factor receptor as a target for cancer therapy. Endocr. Relat. Cancer, 2001, 8(1), 3-9.
[http://dx.doi.org/10.1677/erc.0.0080003] [PMID: 11350723]
[18]
Mehra, R.; Cohen, R.B.; Burtness, B.A. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin. Adv. Hematol. Oncol., 2008, 6(10), 742-750.
[PMID: 18997665]
[19]
Janmaat, M.L.; Giaccone, G. Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors; Alpha Med. Press, 2003.
[http://dx.doi.org/10.1634/theoncologist.8-6-576]
[20]
Hynes, N.E.; Lane, H.A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer, 2005, 5(5), 341-354.
[http://dx.doi.org/10.1038/nrc1609] [PMID: 15864276]
[21]
Pérez-Soler, R. HER1/EGFR targeting: refining the strategy. Oncologist, 2004, 9(1), 58-67.
[http://dx.doi.org/10.1634/theoncologist.9-1-58] [PMID: 14755015]
[22]
Wang, X.; Batty, K.M.; Crowe, P.J.; Goldstein, D.; Yang, J.L. The potential of panHER inhibition in cancer. Front. Oncol., 2015, 5, 2.
[http://dx.doi.org/10.3389/fonc.2015.00002] [PMID: 25674538]
[23]
Egloff, A.M.; Grandis, J.R. Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Semin. Oncol., 2008, 35(3), 286-297.
[http://dx.doi.org/10.1053/j.seminoncol.2008.03.008] [PMID: 18544443]
[24]
World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. J. Am. Coll. Dent., 2014, 81(3), 14-18.
[PMID: 25951678]
[25]
Franceschini, A.; Szklarczyk, D.; Frankild, S.; Kuhn, M.; Simonovic, M. Roth.; Lin, J.; Minguez, P.; Bork, P.; von Mering, C.; Jensen, L.J. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res., 2013, 41(Database issue), D808-D815.
[PMID: 23203871]
[26]
Ahmed, M.F.; Youns, M. Synthesis and biological evaluation of a novel series of 6,8-dibromo-4(3H)quinazolinone derivatives as anticancer agents. Arch. Pharm. (Weinheim), 2013, 346(8), 610-617.
[http://dx.doi.org/10.1002/ardp.201300158] [PMID: 23873839]
[27]
Ismail, M.A.; Barker, S.; Abou el-Ella, D.A.; Abouzid, K.A.; Toubar, R.A.; Todd, M.H. Design and synthesis of new tetrazolyl- and carboxy-biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II AT1 receptor antagonists. J. Med. Chem., 2006, 49(5), 1526-1535.
[http://dx.doi.org/10.1021/jm050232e] [PMID: 16509571]
[28]
Wattanapiromsakul, C.; Forster, P.I.; Waterman, P.G. Alkaloids and limonoids from Bouchardatia neurococca: systematic significance. Phytochemistry, 2003, 64(2), 609-615.
[http://dx.doi.org/10.1016/S0031-9422(03)00205-X] [PMID: 12943784]
[29]
Miknis, G.; Wallace, E.; Lyssikatos, J.; Lee, P.; Zhao, Q.; Hans, J.; Topalov, G.; Buckmelter, A.; Tarlton, G.; Ren, Li.; Tullis, J.; Bernat, B.; Opie, L.P.; Carlowitz, I.V.; Parry, J.; Morales, T.; Perrier, M.; Woessner, R.; Pheneger, T.; Hoffman, K.; Winkler, J.; Koch, K. ARRY-334543, a potent, orally active small molecule inhibitor of EGFR and ErbB-2. Cancer Res., 2005, 65(9), Suppl., 801.
[30]
Liu, C.Y.; Chu, P.Y.; Huang, C.T.; Chen, J.L.; Yang, H.P.; Wang, W.L.; Lau, K.Y.; Lee, C.H.; Lan, T.Y.; Huang, T.T.; Lin, P.H.; Dai, M.S.; Tseng, L.M. Varlitinib downregulates HER/ERK signaling and induces apoptosis in triple negative breast cancer cells. Cancers (Basel), 2019, 11(1)E105
[http://dx.doi.org/10.3390/cancers11010105] [PMID: 30658422]
[31]
Lee, S.C.; Peneyra, J.L.; Rau, K.M. A multicenter phase 2 trial of varlitinib versus lapatinib in combination with capecitabine in patients with HER2+ metastatic breast cancer (MBC) who failed prior trastuzumab therapy. Annals. Oncol., 2017, 28(8)
[32]
Gusscott, S.; Jenkins, C.E.; Lam, S.H.; Giambra, V.; Pollak, M.; Weng, A.P. IGF1R derived PI3K/AKT signaling maintains growth in a subset of human T-cell acute lymphoblastic leukemias. PLoS One, 2016, 11(8)e0161158
[http://dx.doi.org/10.1371/journal.pone.0161158] [PMID: 27532210]
[33]
Chakravarti, A.; Loeffler, J.S.; Dyson, N.J. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res., 2002, 62(1), 200-207.
[PMID: 11782378]
[34]
Maki, R.G. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J. Clin. Oncol., 2010, 28(33), 4985-4995.
[http://dx.doi.org/10.1200/JCO.2009.27.5040] [PMID: 20975071]
[35]
Werner, H.; Bruchim, I. The insulin-like growth factor-I receptor as an oncogene. Arch. Physiol. Biochem., 2009, 115(2), 58-71.
[http://dx.doi.org/10.1080/13813450902783106] [PMID: 19485702]
[36]
Devipriyaa, B.S.; Boby, K.J. Insulin-like growth factor-1 receptor expression in oral squamous cell carcinoma. J. Clin. Exp. Investig, 2011, 2(4), 354-361.
[37]
Harris, C.C. p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment. Environ. Health Perspect., 1996, 104(3), 435-439.
[38]
Lane, D.P. Cancer. p53, guardian of the genome. Nature, 1992, 358(6381), 15-16.
[http://dx.doi.org/10.1038/358015a0] [PMID: 1614522]
[39]
Hollstein, M.; Sidransky, D.; Vogelstein, B.; Harris, C.C. p53 mutations in human cancers. Science, 1991, 253(5015), 49-53.
[http://dx.doi.org/10.1126/science.1905840] [PMID: 1905840]
[40]
Rothenberg, S.M.; Ellisen, L.W. The molecular pathogenesis of head and neck squamous cell carcinoma. J. Clin. Invest., 2012, 122(6), 1951-1957.
[http://dx.doi.org/10.1172/JCI59889] [PMID: 22833868]
[41]
Werner, H.; Sarfstein, R.; LeRoith, D.; Bruchim, I. Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front. Oncol., 2016, 6, 159-169.
[http://dx.doi.org/10.3389/fonc.2016.00159] [PMID: 27446805]
[42]
Chen, Y.Q.; Cipriano, S.C.; Arenkiel, J.M.; Miller, F.R. Tumor suppression by p21WAF1. Cancer Res., 1995, 55(20), 4536.
[PMID: 7553623]
[43]
Fritah, A.; Saucier, C.; Mester, J.; Redeuilh, G.; Sabbah, M. p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha. Mol. Cell. Biol., 2005, 25(6), 2419-2430.
[http://dx.doi.org/10.1128/MCB.25.6.2419-2430.2005] [PMID: 15743834]
[44]
McGowan, E.M.; Tran, N.; Alling, N.; Yagoub, D.; Sedger, L.M.; Martiniello-Wilks, R. p14ARF post-transcriptional regulation of nuclear cyclin D1 in MCF-7 breast cancer cells: discrimination between a good and bad prognosis? PLoS One, 2012, 7(7)e42246
[http://dx.doi.org/10.1371/journal.pone.0042246] [PMID: 22860097]
[45]
Reddy, K.B.; Keshamouni, V.G.; Chen, Y.Q. The level of tyrosine kinase activity regulates the expression of p21/WAF1 in cancer cells. Int. J. Oncol., 1999, 15(2), 301-306.
[http://dx.doi.org/10.3892/ijo.15.2.301] [PMID: 10402241]
[46]
Yang, H.Y.; Wen, Y.Y.; Lin, Y.I.; Pham, L.; Su, C.H.; Yang, H.; Chen, J.; Lee, M.H. Roles for negative cell regulator 14-3-3sigma in control of MDM2 activities. Oncogene, 2007, 26(52), 7355-7362.
[http://dx.doi.org/10.1038/sj.onc.1210540] [PMID: 17546054]
[47]
Ralhan, R.; Masui, O.; Desouza, L.V.; Matta, A.; Macha, M.; Siu, K.W. Identification of proteins secreted by head and neck cancer cell lines using LC-MS/MS: strategy for discovery of candidate serological biomarkers. Proteomics, 2011, 11(12), 2363-2376.
[http://dx.doi.org/10.1002/pmic.201000186] [PMID: 21598386]


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VOLUME: 17
ISSUE: 1
Year: 2020
Published on: 06 January, 2020
Page: [51 - 58]
Pages: 8
DOI: 10.2174/1570164616666190516114749
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