Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

The Correlation between EGFR and Androgen Receptor Pathways: A Novel Potential Prognostic Marker in Gastric Cancer

Author(s): Shahrzad S. Fard, Kioomars Saliminejad, Masoud Sotoudeh, Niloofar Soleimanifard, Shaghayegh Kouchaki, Mansour Yazdanbod, Habibollah Mahmoodzadeh, Ardeshir Ghavamzadeh, Reza Malekzadeh, Bahram Chahardouli, Kamran Alimoghaddam* and Seyed H. Ghaffari*

Volume 19, Issue 17, 2019

Page: [2097 - 2107] Pages: 11

DOI: 10.2174/1871520619666190930142820

Price: $65

Abstract

Background: Despite worthy biologic rationale and numerous studies introducing therapeutic strategies targeting Epidermal Growth Factor Receptor (EGFR), phase III clinical trials have claimed that these current anti-EGFR agents did not significantly improve overall survival of Gastric Cancer (GC) patients. Therefore, to discover flawless candidates of anti-EGFR therapy and ideal prognostic markers, innovative studies are warranted.

Methods: The aim of this study was to assess the expression profile of EGFR in GC, adjacent non-tumor and normal gastric tissues by qRT-PCR, investigating the association of EGFR expression with clinicopathological features, evaluating possible molecular interaction between EGFR and Androgen Receptor (AR), and elucidating novel prognostic marker using Cox regression model.

Results: Among 60 GC patients, 70% (42/60) overexpressed EGFR relative to normal gastric tissues. EGFR overexpression was significantly correlated with the AR overexpression in GC patients. Although EGFR overexpression was remarkably associated with unfavorable outcomes (HR= 4.067, 95% CI= 1.228-13.467, p= 0.022), it was not an independent prognostic factor adjusted for other variables. However, we provided evidences that simultaneous evaluation of EGFR and AR expression, could independently predict the outcome of GC patients and could use as a precise prognostic marker. Moreover, it was revealed that induction or inhibition of AR signaling could alter the mRNA expression of EGFR in GC cell lines.

Conclusion: By targeting AR and EGFR using a potent AR inhibitor such as Enzalutamide, we postulate the possible crosstalk between EGFR and AR pathways in GC. Moreover, our study provided evidences elucidating a novel promising marker, simultaneous evaluation of EGFR and AR expression, which could properly predict prognosis of gastric cancer patients.

Keywords: Epidermal Growth Factor Receptor (EGFR), Androgen Receptor (AR), Gastric Cancer (GC), targeted therapy, prognostic marker, Enzalutamide (ENZ).

« Previous Next »
Graphical Abstract

[1]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[2]
Koizumi, W.; Narahara, H.; Hara, T.; Takagane, A.; Akiya, T.; Takagi, M.; Miyashita, K.; Nishizaki, T.; Kobayashi, O.; Takiyama, W.; Toh, Y.; Nagaie, T.; Takagi, S.; Yamamura, Y.; Yanaoka, K.; Orita, H.; Takeuchi, M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): A phase III trial. Lancet Oncol., 2008, 9(3), 215-221.
[http://dx.doi.org/10.1016/S1470-2045(08)70035-4] [PMID: 18282805]
[3]
Van Cutsem, E.; Moiseyenko, V.M.; Tjulandin, S.; Majlis, A.; Constenla, M.; Boni, C.; Rodrigues, A.; Fodor, M.; Chao, Y.; Voznyi, E.; Risse, M.L.; Ajani, J.A.; Group, V.S. V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J. Clin. Oncol., 2006, 24(31), 4991-4997.
[http://dx.doi.org/10.1200/JCO.2006.06.8429] [PMID: 17075117]
[4]
Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; Aprile, G.; Kulikov, E.; Hill, J.; Lehle, M.; Rüschoff, J.; Kang, Y.K.; To, G.A.T.I. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742), 687-697.
[http://dx.doi.org/10.1016/S0140-6736(10)61121-X] [PMID: 20728210]
[5]
Chen, L.T.; Oh, D.Y.; Ryu, M.H.; Yeh, K.H.; Yeo, W.; Carlesi, R.; Cheng, R.; Kim, J.; Orlando, M.; Kang, Y.K. Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer: A systematic review. Cancer Res. Treat., 2017, 49(4), 851-868.
[http://dx.doi.org/10.4143/crt.2016.176]
[6]
Satoh, T.; Xu, R.H.; Chung, H.C.; Sun, G.P.; Doi, T.; Xu, J.M.; Tsuji, A.; Omuro, Y.; Li, J.; Wang, J.W.; Miwa, H.; Qin, S.K.; Chung, I.J.; Yeh, K.H.; Feng, J.F.; Mukaiyama, A.; Kobayashi, M.; Ohtsu, A.; Bang, Y.J. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J. Clin. Oncol., 2014, 32(19), 2039-2049.
[http://dx.doi.org/10.1200/JCO.2013.53.6136] [PMID: 24868024]
[7]
Ohtsu, A.; Ajani, J.A.; Bai, Y.X.; Bang, Y.J.; Chung, H.C.; Pan, H.M.; Sahmoud, T.; Shen, L.; Yeh, K.H.; Chin, K.; Muro, K.; Kim, Y.H.; Ferry, D.; Tebbutt, N.C.; Al-Batran, S.E.; Smith, H.; Costantini, C.; Rizvi, S.; Lebwohl, D.; Van Cutsem, E. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J. Clin. Oncol., 2013, 31(31), 3935-3943.
[http://dx.doi.org/10.1200/JCO.2012.48.3552] [PMID: 24043745]
[8]
Kanat, O.; O’Neil, B.; Shahda, S. Targeted therapy for advanced gastric cancer: A review of current status and future prospects. World J. Gastrointest. Oncol., 2015, 7(12), 401-410.
[http://dx.doi.org/10.4251/wjgo.v7.i12.401] [PMID: 26690491]
[9]
Zhang, Z.; Tang, H.; Lin, J.; Hu, Y.; Luo, G.; Luo, Z.; Cheng, C.; Wang, P. Clinicopathologic and prognostic significance of human epidermal growth factor receptor in patients with gastric cancer: An updated meta-analysis. Oncotarget, 2017, 8(10), 17202-17215.
[http://dx.doi.org/10.18632/oncotarget.15231] [PMID: 28199988]
[10]
Martinelli, E.; De Palma, R.; Orditura, M.; De Vita, F.; Ciardiello, F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin. Exp. Immunol., 2009, 158(1), 1-9.
[http://dx.doi.org/10.1111/j.1365-2249.2009.03992.x] [PMID: 19737224]
[11]
Mesbahi, Y.; Zekri, A.; Ahmadian, S.; Alimoghaddam, K.; Ghavamzadeh, A.; Ghaffari, S.H. Targeting of EGFR increase anti-cancer effects of arsenic trioxide: Promising treatment for glioblastoma multiform. Eur. J. Pharmacol., 2018, 820, 274-285.
[http://dx.doi.org/10.1016/j.ejphar.2017.12.041] [PMID: 29274334]
[12]
Wang, D.; Wang, B.; Wang, R.; Zhang, Z.; Lin, Y.; Huang, G.; Lin, S.; Jiang, Y.; Wang, W.; Wang, L.; Huang, Q. High expression of EGFR predicts poor survival in patients with resected T3 stage gastric adenocarcinoma and promotes cancer cell survival. Oncol. Lett., 2017, 13(5), 3003-3013.
[http://dx.doi.org/10.3892/ol.2017.5827] [PMID: 28521408]
[13]
Kim, B.J.; Kim, J.H.; Jang, H.J.; Kim, H.S. The role of anti-EGFR agents in the first-line treatment of advanced esophago-gastric adenocarcinoma: A meta-analysis. Oncotarget, 2017, 8(58), 99033-99040.
[http://dx.doi.org/10.18632/oncotarget.20958] [PMID: 29228748]
[14]
Mandel, A.; Larsson, P.; Sarwar, M.; Semenas, J.; Syed Khaja, A.S.; Persson, J.L. The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer. Mol. Med., 2018, 24(1), 34.
[http://dx.doi.org/10.1186/s10020-018-0035-4] [PMID: 30134822]
[15]
Zhang, B.G.; Du, T.; Zang, M.D.; Chang, Q.; Fan, Z.Y.; Li, J.F.; Yu, B.Q.; Su, L.P.; Li, C.; Yan, C.; Gu, Q.L.; Zhu, Z.G.; Yan, M.; Liu, B. Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9. Oncotarget, 2014, 5(21), 10584-10595.
[http://dx.doi.org/10.18632/oncotarget.2513] [PMID: 25301736]
[16]
Tang, W.; Liu, R.; Yan, Y.; Pan, X.; Wang, M.; Han, X.; Ren, H.; Zhang, Z. Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer. Oncotarget, 2017, 8(25), 40765-40777.
[http://dx.doi.org/10.18632/oncotarget.16582] [PMID: 28388558]
[17]
Izumi, K.; Zheng, Y.; Li, Y.; Zaengle, J.; Miyamoto, H. Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. Int. J. Oncol., 2012, 41(5), 1587-1592.
[http://dx.doi.org/10.3892/ijo.2012.1593] [PMID: 22922989]
[18]
Bonaccorsi, L.; Carloni, V.; Muratori, M.; Formigli, L.; Zecchi, S.; Forti, G.; Baldi, E. EGF Receptor (EGFR) signaling promoting invasion is disrupted in androgen-sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR). Int. J. Cancer, 2004, 112(1), 78-86.
[http://dx.doi.org/10.1002/ijc.20362] [PMID: 15305378]
[19]
Ciupek, A.; Rechoum, Y.; Gu, G.; Gelsomino, L.; Beyer, A.R.; Brusco, L.; Covington, K.R.; Tsimelzon, A.; Fuqua, S.A. Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer. Breast Cancer Res. Treat., 2015, 154(2), 225-237.
[http://dx.doi.org/10.1007/s10549-015-3609-7] [PMID: 26487496]
[20]
Zheng, Y.; Izumi, K.; Yao, J.L.; Miyamoto, H. Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells. Endocr. Relat. Cancer, 2011, 18(4), 451-464.
[http://dx.doi.org/10.1530/ERC-11-0010] [PMID: 21613411]
[21]
Schmittgen, T.D.; Livak, K.J. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc., 2008, 3(6), 1101-1108.
[http://dx.doi.org/10.1038/nprot.2008.73] [PMID: 18546601]
[22]
Mateo, J.; Smith, A.; Ong, M.; de Bono, J.S. Novel drugs targeting the androgen receptor pathway in prostate cancer. Cancer Metastasis Rev., 2014, 33(2-3), 567-579.
[http://dx.doi.org/10.1007/s10555-013-9472-2] [PMID: 24390422]
[23]
Moutinho, C.; Mateus, A.R.; Milanezi, F.; Carneiro, F.; Seruca, R.; Suriano, G. Epidermal growth factor receptor structural alterations in gastric cancer. BMC Cancer, 2008, 8, 10.
[http://dx.doi.org/10.1186/1471-2407-8-10] [PMID: 18199332]
[24]
Dragovich, T.; Campen, C. Anti-EGFR-targeted therapy for esophageal and gastric cancers: An evolving concept. J. Oncol., 2009, 2009804108
[http://dx.doi.org/10.1155/2009/804108] [PMID: 19636422]
[25]
Chen, Y.; Guo, S-Y.; Guo, W. The association between EGFR expression and clinical pathology characteristics in gastric cancer. Open Life Sci., 2016, 11(1), 318-321.
[http://dx.doi.org/10.1515/biol-2016-0043]
[26]
Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 2006, 366(1), 2-16.
[http://dx.doi.org/10.1016/j.gene.2005.10.018] [PMID: 16377102]
[27]
Kim, J.S.; Kim, M.A.; Kim, T.M.; Lee, S.H.; Kim, D.W.; Im, S.A.; Kim, T.Y.; Kim, W.H.; Yang, H.K.; Heo, D.S.; Bang, Y.J.; Lee, K.U.; Choe, K.J.; Kim, N.K. Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: Epidermal growth factor receptor (EGFR) associated with favourable survival. Br. J. Cancer, 2009, 100(5), 732-738.
[http://dx.doi.org/10.1038/sj.bjc.6604936] [PMID: 19259093]
[28]
Hong, L.; Han, Y.; Yang, J.; Zhang, H.; Jin, Y.; Brain, L.; Li, M.; Zhao, Q. Prognostic value of epidermal growth factor receptor in patients with gastric cancer: A meta-analysis. Gene, 2013, 529(1), 69-72.
[http://dx.doi.org/10.1016/j.gene.2013.07.106] [PMID: 23954221]
[29]
Lonergan, P.E.; Tindall, D.J. Androgen receptor signaling in prostate cancer development and progression. J. Carcinog., 2011, 10, 20.
[http://dx.doi.org/10.4103/1477-3163.83937] [PMID: 21886458]
[30]
Wang, Q.; Bailey, C.G.; Ng, C.; Tiffen, J.; Thoeng, A.; Minhas, V.; Lehman, M.L.; Hendy, S.C.; Buchanan, G.; Nelson, C.C.; Rasko, J.E.; Holst, J. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res., 2011, 71(24), 7525-7536.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1821] [PMID: 22007000]
[31]
Mukherjee, B.; Mayer, D. Dihydrotestosterone interacts with EGFR/MAPK signalling and modulates EGFR levels in androgen receptor-positive LNCaP prostate cancer cells. Int. J. Oncol., 2008, 33(3), 623-629.
[PMID: 18695894]
[32]
Scher, H.I.; Sawyers, C.L. Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J. Clin. Oncol., 2005, 23(32), 8253-8261.
[http://dx.doi.org/10.1200/JCO.2005.03.4777] [PMID: 16278481]
[33]
Zhang, L.; Fang, C.; Xu, X.; Li, A.; Cai, Q.; Long, X. Androgen receptor, EGFR, and BRCA1 as biomarkers in triple-negative breast cancer: A meta-analysis. BioMed Res. Int., 2015, 2015357485
[http://dx.doi.org/10.1155/2015/357485] [PMID: 25695063]

Rights & Permissions Print Cite
Article Metrics
71
2
© 2024 Bentham Science Publishers | Privacy Policy