Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab

Luistro,Leopoldo  L.; Rosinski,James  A.; Bian,Hongjin; Bishayee,Subal; Rameshwar,Pranela; Ponzio,Nicholas  M.; Ritland,Steve  R.

doi:10.3892/ijo.2012.1463

Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab

Authors:
- Leopoldo L. Luistro
- James A. Rosinski
- Hongjin Bian
- Subal Bishayee
- Pranela Rameshwar
- Nicholas M. Ponzio
- Steve R. Ritland
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Affiliations: Department of Discovery Oncology, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA, Translational Research Sciences, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA, Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey - New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, NJ 07101, USA, Department of Medicine - Hematology/Oncology, University of Medicine and Dentistry of New Jersey - New Jersey Medical School, Newark, NJ 07101, USA, Pharma Clinical Research and Exploratory Development, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA
Published online on: May 8, 2012 https://doi.org/10.3892/ijo.2012.1463
Pages: 639-651

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Abstract

Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and inhibit the function of the human epidermal growth factor receptor 2 (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, however, still occur in a subset of patients treated with regimens including trastuzumab, despite significant improvements in response rates, survival and quality of life. To investigate the potential mechanisms of acquired therapeutic resistance to trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding changes in gene expression profiles. SKOV-3 HR cells were developed by in vivo serial passaging of parental trastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantation of ‘break-through’ xenograft tumors under trastuzumab treatment, significant and reproducible differences in the effects of trastuzumab treatment between SKOV-3 HR and SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retained HER2 protein expression but were unaffected by the antiproliferative effects of trastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished, despite these cells having more binding sites for trastuzumab. Microarray expression profiling (MEP) was performed to determine the genes involved in the resistance mechanism. Functional analysis revealed the differential expression of genes potentially involved in angiogenesis, metastasis, differentiation and proliferation, such as mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated a marked overexpression of MUC1. Based on these data, we hypothesize that the overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogating the antitumor effects of trastuzumab and thus could contribute to resistance to therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical model system may provide the basis for further investigation of potential clinical mechanisms of resistance to trastuzumab.

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1	Alroy I and Yarden Y: The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 410:83–86. 1997. View Article : Google Scholar
2	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
3	Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancers. Science. 244:707–712. 1989. View Article : Google Scholar : PubMed/NCBI
4	Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM and Hortobagyi GN: The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 14:320–368. 2009.PubMed/NCBI
5	Dawood S, Broglio K, Buzdar AU, Hortobagyi GN and Giordano SH: Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 28:92–98. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA and Horowitz IR: Evaluation of monoclonal anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 21:283–290. 2003. View Article : Google Scholar
7	McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Köbel M, Kalloger SE, Swenerton KD, Huntsman DG, Gilks CB and Miller DM: HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer. 9:4332009. View Article : Google Scholar : PubMed/NCBI
8	Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J and Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 344:783–792. 2001. View Article : Google Scholar : PubMed/NCBI
9	Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G and Slamon DJ: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 17:2639–2648. 1999.
10	Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN and Wolmark N: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 353:1673–1684. 2005. View Article : Google Scholar : PubMed/NCBI
11	Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA and Wolmark N: Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 29:3366–3373. 2011.PubMed/NCBI
12	Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P and Piccart-Gebhart MJ: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 369:29–36. 2007.PubMed/NCBI
13	Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A and Crown J: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 365:1273–1283. 2011. View Article : Google Scholar : PubMed/NCBI
14	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, Rüschoff J and Kang YK: 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
15	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
16	Albanell J and Baselga J: Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect. J Natl Cancer Inst. 93:1830–1832. 2001. View Article : Google Scholar : PubMed/NCBI
17	Nahta R, Takahashi T, Ueno NT, Hung MC and Esteva FJ: p27^Kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64:3981–3986. 2004.
18	Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC and Yu D: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 6:117–127. 2004. View Article : Google Scholar : PubMed/NCBI
19	Nagy P, Friedländer E, Tanner M, Kapanen AI, Carraway KL, Isola J and Jovin TM: Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a Herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 65:473–482. 2005.PubMed/NCBI
20	Dhillon J, Astanehe A, Lee C, Fotovati A, Hu K and Dunn SE: The expression of activated Y-box binding protein-1 serine 102 mediates trastuzumab resistance in breast cancer cells by increasing CD44⁺ cells. Oncogene. 29:6294–6300. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN and Yu D: Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 17:461–469. 2011. View Article : Google Scholar : PubMed/NCBI
22	Fernandes H, Cohen S and Bishayee S: Glycosylation-induced conformational modification positively regulates receptor-receptor association: a study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells. J Biol Chem. 276:5375–5383. 2001. View Article : Google Scholar
23	Meric F, Lee WP, Sahin A, Zhang H, Kung HJ and Hung MC: Expression profile of tyrosine kinases in breast cancer. Clin Cancer Res. 8:361–367. 2002.PubMed/NCBI
24	Unger MA, Rishi M, Clemmer VB, Hartman JL, Keiper EA, Greshock JD, Chodosh LA, Liebman MN and Weber BL: Characterization of adjacent breast tumors using oligonucleotide microarrays. Breast Cancer Res. 3:336–341. 2001. View Article : Google Scholar : PubMed/NCBI
25	Raponi M, Belly RT, Karp JE, Lancet JE, Atkins D and Wang Y: Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia. BMC Cancer. 4:562004. View Article : Google Scholar : PubMed/NCBI
26	Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM and Fox JA: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 26(Suppl): 60–70. 1999.PubMed/NCBI
27	Schroeder JA, Thompson MC, Gardner MM and Gendler SJ: Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J Biol Chem. 276:13057–13064. 2001. View Article : Google Scholar : PubMed/NCBI
28	Nielsen DL, Andersson M and Kamby C: HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev. 35:121–136. 2009. View Article : Google Scholar : PubMed/NCBI
29	du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U and Kerbel RS: Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res. 12:904–916. 2006.
30	Fessler SP, Wotkowicz MT, Mahanta SK and Bamdad C: MUC1^* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res Treat. 118:113–124. 2009.
31	Valabrega G, Capellero S, Cavalloni G, Zaccarello G, Petrelli A, Migliardi G, Milani A, Peraldo-Neia C, Gammaitoni L, Sapino A, Pecchioni C, Moggio A, Giordano S, Aglietta M and Montemurro F: HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Res Treat. 130:29–40. 2011. View Article : Google Scholar : PubMed/NCBI
32	Ramanathan RK, Hwang JJ, Zamboni WC, Sinicrope FA, Safran H, Wong MK, Earle M, Brufsky A, Evans T, Troetschel M, Walko C, Day R, Chen HX and Finkelstein S: Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial Cancer Invest. 22:858–865. 2004. View Article : Google Scholar : PubMed/NCBI
33	Pietras RJ, Fendly BM, Chazin VR, Pegram MD, Howell SB and Slamon DJ: Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cells. Oncogene. 9:1829–1838. 1994.PubMed/NCBI
34	Ritter CA, Bianco R, Dugger T, Forbes J, Qu S, Rinehart C, King W and Arteaga CL: Mechanisms of resistance development against trastuzumab (Herceptin) in an in vivo breast cancer model. Int J Clin Pharmacol Ther. 42:642–643. 2004. View Article : Google Scholar : PubMed/NCBI
35	O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O’Donovan N and Slamon DJ: Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 9:1489–1502. 2010.PubMed/NCBI
36	Scheuer W, Freiss 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
37	Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ and Press M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 20:719–726. 2002. View Article : Google Scholar : PubMed/NCBI
38	Reim F, Dombrowski Y, Ritter C, Buttmann M, Häusler S, Ossadnik M, Krockenberger M, Beier D, Beier CP, Dietl J, Becker JC, Hönig A and Wischhusen J: Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells: selective escape of CD44^high/CD24^low/HER2^low breast cancer stem cells. Cancer Res. 69:8058–8066. 2009. View Article : Google Scholar : PubMed/NCBI
39	Packer LM, Williams SJ, Callaghan S, Gotley DC and McGuckin MA: Expression of the cell surface mucin gene family in adenocarcinomas. Int J Oncol. 25:1119–1126. 2004.PubMed/NCBI
40	Scibetta AG, Albanese I, Morris J, Cooper L, Downward J, Rowe P and Taylor-Papadimitriou J: Regulation of MUC1 expression in human mammary cell lines by the c-ErbB2 and ras signaling pathways. DNA Cell Biol. 20:265–274. 2001. View Article : Google Scholar : PubMed/NCBI
41	Hollingsworth MA and Swanson BJ: Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 4:45–60. 2004. View Article : Google Scholar : PubMed/NCBI
42	Li Y, Kuwahara H, Ren J, Wen G and Kufe D: The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin. J Biol Chem. 276:6061–6064. 2001. View Article : Google Scholar : PubMed/NCBI
43	Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P and Gianni L: 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
44	Krop IE, LoRusso O, Miller KD, Modi S, Yardley D, Rodriguez G, Lu M, Burrington B, Agresta S and Rugo H: A phase 2 study of the HER2 antibody-drug conjugate trastuzumab-DM1 (TDM-1) in patients (PTS) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab, lapatinib, and chemotherapy [abstract 2770]. Ann Oncol. 21(Suppl 8): viii972010.
45	Burris HA III, 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 and O’Shaughnessy JA: 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. 29:398–405. 2011. View Article : Google Scholar : PubMed/NCBI
46	Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ, Keith BR, Gilmer TM, Berger M, Podratz KC and Slamon DJ: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 66:1630–1639. 2006. View Article : Google Scholar : PubMed/NCBI
47	Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S and Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 355:2733–2743. 2006. View Article : Google Scholar : PubMed/NCBI