Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody–cytotoxic drug conjugate
- 115 Downloads
Trastuzumab emtansine (T-DM1) provides clinical benefit in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). However, its efficacy against biliary tract cancers (BTC) has not been evaluated. In this study, the effectiveness of T-DM1 in various BTC cell lines and xenograft models with different levels of HER2 expression was investigated.
HER2 expression status in xenografts and patient tissue microarrays was assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Cell-surface HER2 expression levels and cell growth inhibition in response to T-DM1 were examined in 17 BTC cell lines. The antitumor activity of T-DM1 was evaluated in four xenograft mouse models with different levels of HER2 expression. The effects of T-DM1 on HER2 signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), cell cycle, and apoptosis were assessed in vitro.
Cell-surface expression of HER2 was observed in both gallbladder carcinoma and cholangiocarcinoma tissues. The anti-proliferative activity of T-DM1 was higher in BTC cell lines and breast cancer cell lines with higher levels of HER2 expression. The HER2 status (IHC score|HER2-to-CEP17 ratio by FISH testing) of each BTC xenograft was 3 +|8.3 for KMCH-1, 2 +|4.7 for Mz-ChA-1, 1 +/0|1.4 for OCUG-1, and 0|1.1 for KKU-100, and T-DM1 showed antitumor activity in proportion to the HER2 status. T-DM1 inhibited HER2 signaling and induced ADCC, mitotic arrest, and apoptosis in KMCH-1 cells.
T-DM1 exhibited preclinical activity in HER2-overexpressing BTC. Further evaluation in clinical studies is warranted.
KeywordsT-DM1 Trastuzumab emtansine HER2 Biliary tract cancer
We thank Marie Mochizuki and Mirei Kouno (Product Research Department, Chugai Pharmaceutical Co., Ltd.) for technical assistance; Dr. Kaori Fujimoto-Ouchi (Product Research Department, Chugai Pharmaceutical Co., Ltd.) for helpful suggestions and comments about this study; and Dr. Banchob Spira (Khon Kaen University) for kindly providing KKU-100, KKU-055 and KKU-0213 cell lines.
Compliance with ethical standards
Conflict of interest
Junichi Shoda received research fee and grants from Chugai Pharmaceutical Co., Ltd. and other authors have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at Chugai Pharmaceuticals, Co., Ltd. and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The human tissues were processed anonymously inhibiting the revelation of the donor’s identity.
- 2.Recio-Boiles A, Babiker HM (2017) Cancer, gallbladder. In: StatPearls. StatPearls, Treasure IslandGoogle Scholar
- 8.Terashima M, Kitada K, Ochiai A, Ichikawa W, Kurahashi I, Sakuramoto S, Katai H, Sano T, Imamura H, Sasako M, Group A-G (2012) Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin Cancer Res 18(21):5992–6000. https://doi.org/10.1158/1078-0432.CCR-12-1318 CrossRefGoogle Scholar
- 11.Kawamoto T, Ishige K, Thomas M, Yamashita-Kashima Y, Shu S, Ishikura N, Ariizumi S, Yamamoto M, Kurosaki K, Shoda J (2015) Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab. J Gastroenterol 50(4):467–479. https://doi.org/10.1007/s00535-014-0984-5 CrossRefGoogle Scholar
- 12.Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blattler WA (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66(8):4426–4433. https://doi.org/10.1158/0008-5472.can-05-4489 CrossRefGoogle Scholar
- 14.Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H, Kovtun Y, Chari R, Jordan MA (2010) Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther 9(10):2700–2713. https://doi.org/10.1158/1535-7163.mct-10-0645 CrossRefGoogle Scholar
- 15.Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX (2011) 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(2):347–356. https://doi.org/10.1007/s10549-010-1090-x CrossRefGoogle Scholar
- 17.Yamashita-Kashima Y, Iijima S, Yorozu K, Furugaki K, Kurasawa M, Ohta M, Fujimoto-Ouchi K (2011) Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res 17(15):5060–5070. https://doi.org/10.1158/1078-0432.CCR-10-2927 CrossRefGoogle Scholar
- 18.Yamashita-Kashima Y, Shu S, Yorozu K, Hashizume K, Moriya Y, Fujimoto-Ouchi K, Harada N (2014) Importance of formalin fixing conditions for HER2 testing in gastric cancer: immunohistochemical staining and fluorescence in situ hybridization. Gastric Cancer 17(4):638–647. https://doi.org/10.1007/s10120-013-0329-8 CrossRefGoogle Scholar
- 19.Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for Human Epidermal Growth Factor Receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 31(31):3997–4013. https://doi.org/10.1200/JCO.2013.50.9984 CrossRefGoogle Scholar
- 21.Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, Salo J, Joensuu H, Sihvo E, Elenius K, Isola J (2005) Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIα gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 16(2):273–278. https://doi.org/10.1093/annonc/mdi064 CrossRefGoogle Scholar
- 25.Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW, Holden SN, Modi S (2012) A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 118(23):5733–5740. https://doi.org/10.1002/cncr.27622 CrossRefGoogle Scholar
- 26.Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68(22):9280–9290. https://doi.org/10.1158/0008-5472.can-08-1776 CrossRefGoogle Scholar
- 27.Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blättler WA (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66(8):4426–4433. https://doi.org/10.1158/0008-5472.can-05-4489 CrossRefGoogle Scholar
- 29.Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29(4):398–405. https://doi.org/10.1200/jco.2010.29.5865 CrossRefGoogle Scholar
- 32.Cretella D, Saccani F, Quaini F, Frati C, Lagrasta C, Bonelli M, Caffarra C, Cavazzoni A, Fumarola C, Galetti M, La Monica S, Ampollini L, Tiseo M, Ardizzoni A, Petronini PG, Alfieri RR (2014) Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance. Mol Cancer 13:143. https://doi.org/10.1186/1476-4598-13-143 CrossRefGoogle Scholar
- 33.Hayashi T, Seiler R, Oo HZ, Jager W, Moskalev I, Awrey S, Dejima T, Todenhofer T, Li N, Fazli L, Matsubara A, Black PC (2015) Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is Effective in HER2 over expressing bladder cancer. J Urol 194(4):1120–1131. https://doi.org/10.1016/j.juro.2015.05.087 CrossRefGoogle Scholar
- 35.Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) 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(9742):687–697. https://doi.org/10.1016/s0140-6736(10)61121-x CrossRefGoogle Scholar
- 36.Van Cutsem E, Bang Y-J, Feng-yi F, Xu JM, Lee K-W, Jiao S-C, Chong JL, López-Sanchez RI, Price T, Gladkov O, Stoss O, Hill J, Ng V, Lehle M, Thomas M, Kiermaier A, Rüschoff J (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18(3):476–484. https://doi.org/10.1007/s10120-014-0402-y CrossRefGoogle Scholar