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Article

Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model

  • Authors:
    • Yoriko Yamashita-Kashima
    • Sei Shu
    • Naoki Harada
    • Kaori Fujimoto-Ouchi
  • View Affiliations / Copyright

    Affiliations: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan
  • Pages: 1087-1093
    |
    Published online on: June 19, 2013
       https://doi.org/10.3892/or.2013.2547
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Abstract

Human epidermal growth factor receptor 2 (HER2)-targeted therapy by trastuzumab has become increasingly important for treating HER2-positive cancers, and trastuzumab emtansine (T-DM1) is expected to serve as an effective alternative to trastuzumab. Pertuzumab, a HER2 dimerization inhibitor, showed prolonged progression-free survival when used with trastuzumab for HER2-positive breast cancer. In this study, we investigated the effect of combining T-DM1 and pertuzumab on xenografted gastric tumors. T-DM1 as a single agent showed significant antitumor activity in all the three HER2-high expression tumor models tested (NCI-N87, SCH and 4-1ST) but was ineffective against two HER2-low expression tumors (SNU-16 and MKN-28). Using the T-DM1-sensitive NCI-N87 model, the combination efficacy of T-DM1 and pertuzumab was elucidated. The combination induced significant tumor regression, whereas T-DM1 or pertuzumab alone did not. In cultured NCI-N87 cells stimulated with epidermal growth factor (EGF) or heregulin-α, concomitant treatment of T-DM1 and pertuzumab significantly inhibited proliferation and increased caspase 3/7 activity compared to either agent alone. Only the combination significantly inhibited the phosphorylation of EGFR or HER3, and its downstream factor AKT. Suppressed HER3 phosphorylation by the combination was also seen in the NCI-N87 xenografted tumors. Compared to single agent treatments, the combination treatment significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) against NCI-N87 cells. These findings suggest that T-DM1 in combination with pertuzumab shows significant antitumor activity by increasing AKT signal inhibition and ADCC in HER2-positive gastric cancers.
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1 

Garcia I, Vizoso F, Martin A, et al: Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol. 10:234–241. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Yonemura Y, Ninomiya I, Yamaguchi A, et al: Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 51:1034–1038. 1991.PubMed/NCBI

3 

Tanner M, Hollmen M, Junttila TT, et al: Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 16:273–278. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Nicholson RI, Gee JM and Harper ME: EGFR and cancer prognosis. Eur J Cancer. 37(Suppl 4): S9–S15. 2001. View Article : Google Scholar

5 

Hayashi M, Inokuchi M, Takagi Y, et al: High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res. 14:7843–7849. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Bang YJ, Van Cutsem E, Feyereislova A, et al: 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. 376:687–697. 2010. View Article : Google Scholar

7 

Kovtun YV and Goldmacher VS: Cell killing by antibody-drug conjugates. Cancer Lett. 255:232–240. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Lewis Phillips GD, Li G, Dugger DL, et al: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68:9280–9290. 2008.PubMed/NCBI

9 

Erickson HK, Lewis Phillips GD, Leipold DD, et al: The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 11:1133–1142. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Oroudjev E, Lopus M, Wilson L, et al: Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther. 9:2700–2713. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Lopus M, Oroudjev E, Wilson L, et al: Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 9:2689–2699. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Junttila TT, Li G, Parsons K, Phillips GL and Sliwkowski MX: Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 128:347–356. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Barok M, Tanner M, Koninki K and Isola J: Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 306:171–179. 2011. View Article : Google Scholar : PubMed/NCBI

14 

LoRusso PM, Weiss D, Guardino E, Girish S and Sliwkowski MX: Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 17:6437–6447. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM and Sliwkowski MX: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 5:317–328. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 366:109–119. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Yamashita-Kashima Y, Iijima S, Yorozu K, et al: Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res. 17:5060–5070. 2011. View Article : Google Scholar

18 

Fujimoto-Ouchi K, Sekiguchi F, Yasuno H, Moriya Y, Mori K and Tanaka Y: Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol. 59:795–805. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Fujimoto-Ouchi K, Sekiguchi F and Tanaka Y: Antitumor activity of combinations of anti-HER-2 antibody trastuzumab and oral fluoropyrimidines capecitabine/5′-dFUrd in human breast cancer models. Cancer Chemother Pharmacol. 49:211–216. 2002.PubMed/NCBI

20 

Baselga J, Gelmon KA, Verma S, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 28:1138–1144. 2010. View Article : Google Scholar

21 

Hurvitz SA, Dirix L, Kocsis J, Gianni L, Lu MJ, Vinholes J, Song C, Tong B, Chu Y-W and Perez EA: Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/BO21976). Eur J Cancer. 47:S3302011. View Article : Google Scholar

22 

Baselga J and Swain SM: Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 9:463–475. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Olayioye MA, Neve RM, Lane HA and Hynes NE: The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 19:3159–3167. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Spector NL and Blackwell KL: Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 27:5838–5847. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J and Hasmann M: Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69:9330–9336. 2009. View Article : Google Scholar

26 

El-Sahwi K, Bellone S, Cocco E, et al: In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer. 102:134–143. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yamashita-Kashima Y, Shu S, Harada N and Fujimoto-Ouchi K: Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncol Rep 30: 1087-1093, 2013.
APA
Yamashita-Kashima, Y., Shu, S., Harada, N., & Fujimoto-Ouchi, K. (2013). Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncology Reports, 30, 1087-1093. https://doi.org/10.3892/or.2013.2547
MLA
Yamashita-Kashima, Y., Shu, S., Harada, N., Fujimoto-Ouchi, K."Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model". Oncology Reports 30.3 (2013): 1087-1093.
Chicago
Yamashita-Kashima, Y., Shu, S., Harada, N., Fujimoto-Ouchi, K."Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model". Oncology Reports 30, no. 3 (2013): 1087-1093. https://doi.org/10.3892/or.2013.2547
Copy and paste a formatted citation
x
Spandidos Publications style
Yamashita-Kashima Y, Shu S, Harada N and Fujimoto-Ouchi K: Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncol Rep 30: 1087-1093, 2013.
APA
Yamashita-Kashima, Y., Shu, S., Harada, N., & Fujimoto-Ouchi, K. (2013). Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncology Reports, 30, 1087-1093. https://doi.org/10.3892/or.2013.2547
MLA
Yamashita-Kashima, Y., Shu, S., Harada, N., Fujimoto-Ouchi, K."Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model". Oncology Reports 30.3 (2013): 1087-1093.
Chicago
Yamashita-Kashima, Y., Shu, S., Harada, N., Fujimoto-Ouchi, K."Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model". Oncology Reports 30, no. 3 (2013): 1087-1093. https://doi.org/10.3892/or.2013.2547
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