A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

Abstract

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

Keywords

epidermal growth factor receptor / ErbB receptors / HM781-36B / nasopharyngeal carcinoma / molecular targeted therapy / cisplatin

References

[1] Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet 2019; 394(10192): 64–80

[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394–424

[3] Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, Adkins D, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Eisele DW, Fenton M, Foote RL, Gilbert J, Gillison ML, Haddad RI, Hicks WL Jr, Hitchcock YJ, Jimeno A, Leizman D, Maghami E, Mell LK, Mittal BB, Pinto HA, Ridge JA, Rocco J, Rodriguez CP, Shah JP, Weber RS, Witek M, Worden F, Zhen W, Burns JL, Darlow SD. NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018. J Natl Compr Canc Netw 2018; 16(5): 479–490

[4] Ali SM, Yao M, Yao J, Wang J, Cheng Y, Schrock AB, Chirn GW, Chen H, Mu S, Gay L, Elvin JA, Suh J, Miller VA, Stephens PJ, Ross JS, Wang K. Comprehensive genomic profiling of different subtypes of nasopharyngeal carcinoma reveals similarities and differences to guide targeted therapy. Cancer 2017; 123(18): 3628–3637

[5] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2(2): 127–137

[6] Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 2014; 25(3): 282–303

[7] Leong JL, Loh KS, Putti TC, Goh BC, Tan LK. Epidermal growth factor receptor in undifferentiated carcinoma of the nasopharynx. Laryngoscope 2004; 114(1): 153–157

[8] Taheri-Kadkhoda Z, Magnusson B, Svensson M, Mercke C, Björk-Eriksson T. Expression modes and clinical manifestations of latent membrane protein 1, Ki-67, cyclin-B1, and epidermal growth factor receptor in nonendemic nasopharyngeal carcinoma. Head Neck 2009; 31(4): 482–492

[9] Miller WE, Earp HS, Raab-Traub N. The Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor. J Virol 1995; 69(7): 4390–4398

[10] Bar-Sela G, Kuten A, Ben-Eliezer S, Gov-Ari E, Ben-Izhak O. Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach. Mod Pathol 2003; 16(10): 1035–1040

[11] Roychowdhury DF, Tseng A Jr, Fu KK, Weinburg V, Weidner N. New prognostic factors in nasopharyngeal carcinoma. Tumor angiogenesis and C-erbB2 expression. Cancer 1996; 77(8): 1419–1426

[12] Duan B, Zhu Z, You B, Shi S, Shan Y, Jiang P, Zhang Q, Bao L, Yin Y, You Y. Overexpression of ERBB3 promotes proliferation, migration, and angiogenesis in nasopharyngeal carcinoma. Int J Clin Exp Pathol 2019; 12(8): 2931–2940

[13] Kang MH, Moon SU, Sung JH, Kim JW, Lee KW, Lee HS, Lee JS, Kim JH. Antitumor activity of HM781-36B, alone or in combination with chemotherapeutic agents, in colorectal cancer cells. Cancer Res Treat 2016; 48(1): 355–364

[14] Wang M, Hu Y, Yu T, Ma X, Wei X, Wei Y. Pan-HER-targeted approach for cancer therapy: mechanisms, recent advances and clinical prospect. Cancer Lett 2018; 439: 113–130

[15] Cha MY, Lee KO, Kim M, Song JY, Lee KH, Park J, Chae YJ, Kim YH, Suh KH, Lee GS, Park SB, Kim MS. Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models. Int J Cancer 2012; 130(10): 2445–2454

[16] Nam HJ, Kim HP, Yoon YK, Hur HS, Song SH, Kim MS, Lee GS, Han SW, Im SA, Kim TY, Oh DY, Bang YJ. Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. Cancer Lett 2011; 302(2): 155–165

[17] Hiraishi Y, Wada T, Nakatani K, Tojyo I, Matsumoto T, Kiga N, Negoro K, Fujita S. EGFR inhibitor enhances cisplatin sensitivity of oral squamous cell carcinoma cell lines. Pathol Oncol Res 2008; 14(1): 39–43

[18] Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel) 2017; 9(5): 52

[19] LamWKJChanJYK. Recent advances in the management of nasopharyngeal carcinoma F1000Res 2018; 7: F1000 Faculty Rev-1829 doi: 10.12688/f1000research.15066.1

[20] Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4(5): 361–370

[21] Ma BB, Poon TC, To KF, Zee B, Mo FK, Chan CM, Ho S, Teo PM, Johnson PJ, Chan AT. Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma—a prospective study. Head Neck 2003; 25(10): 864–872

[22] Lee Y, Cho S, Seo JH, Shin BK, Kim HK, Kim I, Kim A. Correlated expression of erbB-3 with hormone receptor expression and favorable clinical outcome in invasive ductal carcinomas of the breast. Am J Clin Pathol 2007; 128(6): 1041–1049

[23] Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE. The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res 2006; 66(12): 6412–6420

[24] Tang CK, Concepcion XZ, Milan M, Gong X, Montgomery E, Lippman ME. Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo. Cancer Res 1999; 59(20): 5315–5322

[25] Huang Z, Brdlik C, Jin P, Shepard HM. A pan-HER approach for cancer therapy: background, current status and future development. Expert Opin Biol Ther 2009; 9(1): 97–110

[26] Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5(5): 341–354

[27] Goldberg RM, Kirkpatrick P. Cetuximab. Nat Rev Drug Discov 2005; 4(5 Suppl): S10–S11

[28] Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res 2016; 22(6): 1307–1312

[29] Kim HJ, Kim HP, Yoon YK, Kim MS, Lee GS, Han SW, Im SA, Kim TY, Oh DY, Bang YJ. Antitumor activity of HM781-36B, a pan-HER tyrosine kinase inhibitor, in HER2-amplified breast cancer cells. Anticancer Drugs 2012; 23(3): 288–297

[30] Arwert EN, Harney AS, Entenberg D, Wang Y, Sahai E, Pollard JW, Condeelis JS. A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep 2018; 23(5): 1239–1248

[31] Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, Olson OC, Tazzyman S, Danson S, Addison C, Clemons M, Gonzalez-Angulo AM, Joyce JA, De Palma M, Pollard JW, Lewis CE. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res 2015; 75(17): 3479–3491

[32] Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol 2012; 30(1): 1–22

[33] Veglia F, Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol 2017; 45: 43–51

[34] Ostrand-Rosenberg S. Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 2018; 51: 68–75

[35] Kawano M, Mabuchi S, Matsumoto Y, Sasano T, Takahashi R, Kuroda H, Kozasa K, Hashimoto K, Isobe A, Sawada K, Hamasaki T, Morii E, Kimura T. The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep 2015; 5(1): 18217

Acknowledgements

This work was supported by the National Science Foundation for Excellent Young Scholars (No. 32122052) and National Natural Science Regional Innovation and Development Foundation (No. U19A2003).

Compliance with ethics guidelines

Jing Yang, Yanfei Yang, Yuquan Wei, and Xiawei Wei declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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