Toxicology of Trastuzumab: An Insight into Mechanisms of Cardiotoxicity

Jie       An; M.    Saeed    Sheikh

doi:10.2174/1568009618666171129222159

Abstract

Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is regarded as one of the risk factors for trastuzumab-induced cardiotoxcity. Although it is generally believed that the trastuzumab-induced cardiotoxic effects are reversible, various preclinical studies have revealed its apoptotic effects on cardiomyocytes. Thus, the issue of the reversibility of its cardiotoxic effects remains to be fully resolved. This article discusses various mechanisms that have been proposed for the cardiotoxic effects of trastuzumab and the potential risk factors that can lead to cardiotoxicity. The recently approved anti-HER2 monoclonal antibodies including pertuzumab and ado-trastuzumab (T-DM1) are also discussed.

Keywords: Trastuzumab, Pertuzumab, Ado-trastuzumab, cardiotoxicity, breast cancer, gastric cancer, risk factors.

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[1] 
Vugmeyster, Y.; Xu, X.; Theil, F.P.; Khawli, L.A.; Leach, M.W. Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges. World J. Biol. Chem.,  2012, 3, 73-92.
[2] 
Scott, A.M.; Wolchok, J.D.; Old, L.J. Antibody therapy of cancer. Nat. Rev. Cancer,  2012, 12, 278-287.
[3] 
Chan, A.C.; Carter, P.J. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol.,  2010, 10, 301-316.
[4] 
Carter, P.; Presta, L.; Gorman, C.M.; Ridgway, J.B.; Henner, D.; Wong, W.L.; Rowland, A.M.; Kotts, C.; Carver, M.E.; Shepard, H.M. Humanization of an anti-p185her2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. USA,  1992, 89, 4285-4289.
[5] 
Graus-Porta, D.; Beerli, R.R.; Daly, J.M.; Hynes, N.E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J.,  1997, 16, 1647-1655.
[6] 
Citri, A.; Skaria, K.B.; Yarden, Y. The deaf and the dumb: The biology of ErbB-2 and ErbB-3. Exp. Cell Res.,  2003, 284, 54-65.
[7] 
Wieduwilt, M.J.; Moasser, M.M. The epidermal growth factor receptor family: Biology driving targeted therapeutics. Cell. Mol. Life Sci.,  2008, 65, 1566-1584.
[8] 
Pinkas-Kramarski, R.; Soussan, L.; Waterman, H.; Levkowitz, G.; Alroy, I.; Klapper, L.; Lavi, S.; Seger, R.; Ratzkin, B.J.; Sela, M.; Yarden, Y. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J.,  1996, 15, 2452-2467.
[9] 
Pohlmann, P.R.; Mayer, I.A.; Mernaugh, R. Resistance to trastuzumab in breast cancer. Clin. Cancer Res.,  2009, 15, 7479-7491.
[10] 
Baselga, J. Clinical trials of herceptin (Trastuzumab). Eur. J. Cancer,  2001, 37(Suppl. 1), S18-S24.
[11] 
 Herceptin, full prescribing information, revised April, 2017,
                    https://www.gene.com/download/pdf/herceptin_prescribing.pdf
                (Accessed Sep 19, 2017).
[12] 
 Herceptin,
                    http://www.herceptin.com/
                (Accessed Sep 19, 2017).
[13] 
Molina, M.A.; Codony-Servat, J.; Albanell, J.; Rojo, F.; Arribas, J.; Baselga, J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res.,  2001, 61, 4744-4749.
[14] 
Onitilo, A.A.; Engel, J.M.; Stankowski, R.V. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: Prevalence, patient characteristics, and risk factors. Ther. Adv. Drug Saf.,  2014, 5, 54-66.
[15] 
Vermeulen, Z.; Segers, V.F.; De Keulenaer, G.W. ErbB2 signaling at the crossing between heart failure and cancer. Basic Res. Cardiol.,  2016, 111, 60.
[16] 
De Keulenaer, G.W.; Doggen, K.; Lemmens, K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ. Res.,  2010, 106, 35-46.
[17] 
Zeglinski, M.; Ludke, A.; Jassal, D.S.; Singal, P.K. Trastuzumab-induced cardiac dysfunction: A ‘dual-hit’. Exp. Clin. Cardiol.,  2011, 16, 70-74.
[18] 
Ewer, M.S.; Vooletich, M.T.; Durand, J.B.; Woods, M.L.; Davis, J.R.; Valero, V.; Lenihan, D.J. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J. Clin. Oncol.,  2005, 23, 7820-7826.
[19] 
Telli, M.L.; Hunt, S.; Carlson, R.W.; Guardino, A.E. Trastuzumab-related cardiotoxicity: Calling into question the concept of reversibility. J. Clin. Oncol.,  2007, 25, 3525-3533.
[20] 
ElZarrad, M.K.; Mukhopadhyay, P.; Mohan, N.; Hao, E.; Dokmanovic, M.; Hirsch, D.S.; Shen, Y.; Pacher, P.; Wu, W.J. Trastuzumab alters the expression of genes essential for cardiac function and induces ultrastructural changes of cardiomyocytes in mice. PLoS One,  2013, 8, e79543.
[21] 
Barth, A.S.; Zhang, Y.; Li, T.; Smith, R.R.; Chimenti, I.; Terrovitis, I.; Davis, D.R.; Kizana, E.; Ho, A.S.; O’Rourke, B.; Wolff, A.C.; Gerstenblith, G.; Marbán, E. Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab. Stem Cells Transl. Med.,  2012, 1, 289-297.
[22] 
Mohan, N.; Shen, Y.; Endo, Y.; ElZarrad, M.; Wu, W.J. Trastuzumab, but not pertuzumab, dysregulates HER2 signaling to mediate inhibition of autophagy and increase in reactive oxygen species production in human cardiomyocytes. Mol. Cancer Ther.,  2016, 15, 1321-1331.
[23] 
Rodríguez, C.E.; Reidel, S.I.; Bal de Kier Joffé, E.D.; Jasnis, M.A.; Fiszman, G.L. Autophagy protects from trastuzumab-induced cytotoxicity in HER2 overexpressing breast tumor spheroids. PLoS One,  2015, 10, e0137920.
[24] 
Thomas, R.L.; Roberts, D.J.; Kubli, D.A.; Lee, Y.; Quinsay, M.N.; Owens, J.B.; Fischer, K.M.; Sussman, M.A.; Miyamoto, S.; Gustafsson, A.B. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev.,  2013, 27, 1365-1377.
[25] 
Dirks-Naylor, A.J. The role of autophagy in doxorubicin-induced cardiotoxicity. Life Sci.,  2013, 93(24), 913-916.
[26] 
Lu, L.; Wu, W.; Yan, J.; Li, X.; Yu, H.; Yu, X. Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure. Int. J. Cardiol.,  2009, 134, 82-90.
[27] 
 RxList:
                    http://www.rxlist.com/perjeta-drug.htm
                (accessed Jan 31,
2017).
[28] 
 Perjeta, full prescribing information, revised May, 2017,
                    https://www.gene.com/download/pdf/perjeta_prescribing.pdf
                (accessed
Sep 19, 2017).
[29] 
 Kondapalli, L. Cardiotoxicity: an unexpected consequence of
HER2-targeted therapies. American College of Cardiology, Jun 07,
2016,
                    http://www.acc.org/latest-in-cardiology/articles/2016/ 06/06/ 09/32/cardiotoxicity?w_nav=TI
                (accessed Sep 19, 2017).
[30] 
 Kadcyla, full prescribing information, revised July, 2016,
                    https://www.gene.com/download/pdf/kadcyla_prescribing.pdf
                (accessed Sep 19, 2017).
[31] 
Diessner, J.; Bruttel, V.; Stein, R.G.; Horn, E.; Häusler, S.F.; Dietl, J.; Hönig, A.; Wischhusen, J. Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1). Cell Death Dis.,  2014, 5, e1149.
[32] 
Sendur, M.A.; Aksoy, S.; Altundag, K. Cardiotoxicity of novel HER2-targeted therapies. Curr. Med. Res. Opin.,  2013, 29, 1015-1024.
[33] 
Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.Y.; Diéras, V.; Guardino, E.; Fang, L.; Lu, M.W.; Olsen, S.; Blackwell, K. EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med.,  2012, 367, 1783-1791.
[34] 
Sheikh, M.S. RNA-binding Protein, GADD45-alpha, p27Kip1, p53 and genotoxic stress response in relation to chemoresistance in cancer. Mol. Cell. Pharmacol.,  2015, 7, 41-45.
[35] 
Chu, E.; Sartorelli, A.C. Cancer chemotherapy In: Basic & Clinical
Pharmacology; Katzung B.G.; Trevor A.J., Ed.; McGraw-Hill:
New York; 2015, 13th Ed., pp. 934-935.
[36] 
Cookson, M.S.; Chang, S.S.; Lihou, C.; Li, T.; Harper, S.Q.; Lang, Z.; Tutrone, R.F. Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder. Ther. Adv. Urol.,  2014, 6, 181-191.
[37] 
Cottin, Y.; Touzery, C.; Dalloz, F.; Coudert, B.; Toubeau, M.; Riedinger, A.; Louis, P.; Wolf, J.E.; Brunotte, F. Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studied by radionuclide angiography. Clin. Cardiol.,  1998, 21, 665-670.
[38] 
Jain, K.K.; Casper, E.S.; Geller, N.L.; Hakes, T.B.; Kaufiiiann, R.J.; Currie, V.; Schwartz, W.; Cassidy, C.; Petroni, G.R.; Young, C.W. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J. Clin. Oncol.,  1985, 3, 818-826.
[39] 
Gammella, E.; Maccarinelli, F.; Buratti, P.; Recalcati, S.; Cairo, G. The role of iron in anthracycline cardiotoxicity. Front. Pharmacol.,  2014, 5, 25.
[40] 
Chabner, B.A.; Bertino, J.; Cleary, J.; Ortiz, T.; Lane, A.; Supko, J.G.; Ryan, D.  Cytotoxic Agents. In: Brunton, L.L.; Chabner, B.A.;
Knollmann, B.C. eds. Goodman & Gilman's: The Pharmacological
Basis of Therapeutics, 12e New York, NY: McGraw-
Hill;.
                    http://accessmedicine.mhmedical.com/content.aspx?bookid=1613§ionid=102164019
                (Accessed Sep 19, 2017).
[41] 
Volkova, M.; Russell, R., III Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr. Cardiol. Rev.,  2011, 7, 214-220.
[42] 
Ewer, M.S.; Ewer, S.M. The anthracycline-trastuzumab interaction: a lesson in not jumping to confusion. Trends Pharmacol. Sci.,  2015, 36, 321-322.
[43] 
Zhao, L.; Zhang, B. Doxorubicin induces cardiotoxicity through upregulation of death receptorsmediated apoptosis in cardiomyocytes. Sci. Rep.,  2017, 7, 44735.
[44] 
Chatterjee, K.; Zhang, J.; Honbo, N.; Karliner, J.S. Doxorubicin cardiomyopathy. Cardiology,  2010, 115, 155-162.
[45] 
Farolfi, A.; Melegari, E.; Aquilina, M.; Scarpi, E.; Ibrahim, T.; Maltoni, R.; Sarti, S.; Cecconetto, L.; Pietri, E.; Ferrario, C.; Fedeli, A.; Faedi, M.; Nanni, O.; Frassineti, G.L.; Amadori, D.; Rocca, A. Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart,  2013, 99, 634-639.
[46] 
Cochet, A.; Quilichini, G.; Dygai-Cochet, I.; Touzery, C.; Toubeau, M.; Berriolo-Riedinger, A.; Coudert, B.; Cottin, Y.; Fumoleau, P.; Brunotte, F. Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res. Treat.,  2011, 130, 845-854.
[47] 
Russo, G.; Cioffi, G.; Di Lenarda, A.; Tuccia, F.; Bovelli, D.; Di Tano, G.; Alunni, G.; Gori, S.; Faggiano, P.; Tarantini, L. Role of renal function on development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer. Intern. Emerg. Med.,  2012, 7, 439-446.
[48] 
Lemieux, J.; Diorio, C.; Côté, M.A.; Provencher, L.; Barabé, F.; Jacob, S.; St-Pierre, C.; Demers, E.; Tremblay-Lemay, R.; Nadeau-Larochelle, C.; Michaud, A.; Laflamme, C. Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab. Anticancer Res.,  2013, 33, 569-576.
[49] 
Serrano, C.; Cortés, J.; De Mattos-Arruda, L.; Bellet, M.; Gómez, P.; Saura, C.; Pérez, J.; Vidal, M.; Muñoz-Couselo, E.; Carreras, M.J.; Sánchez-Ollé, G.; Tabernero, J.; Baselga, J.; DiCosimo, S. Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann. Oncol.,  2012, 23, 897-902.
[50] 
Han, W.; Kang, D.; Lee, J.E.; Park, I.A.; Choi, J.Y.; Lee, K.M.; Bae, J.Y.; Kim, S.; Shin, E.S.; Lee, J.E.; Shin, H.J.; Kim, S.W.; Kim, S.W.; Noh, D.Y. A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea. Clin. Cancer Res.,  2005, 11, 4775-4778.
[51] 
Lemmon, M.A.; Schlessinger, J.; Ferguson, K.M. The EGFR family: Not so prototypical receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol.,  2014, 6, a020768.
[52] 
Fleishman, S.J.; Schlessinger, J.; Ben-Tal, N. A putative molecular-activation switch in the transmembrane domain of erbB2. Proc. Natl. Acad. Sci. USA,  2002, 99, 15937-15940.
[53] 
Jorissen, R.N.; Walker, F.; Pouliot, N.; Garrett, T.P.; Ward, C.W.; Burgess, A.W. Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp. Cell Res.,  2003, 284, 31-53.
[54] 
Zhang, X.; Gureasko, J.; Shen, K.; Cole, P.A.; Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell,  2006, 125, 1137-1149.
[55] 
Beauclair, S.; Formento, P.; Fischel, J.L.; Lescaut, W.; Largillier, R.; Chamorey, E.; Hofman, P.; Ferrero, J.M.; Pagès, G.; Milano, G. Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity. Ann. Oncol.,  2007, 18, 1335-1341.
[56] 
Mailliez, A.; Révillion, F.; Ploquin, A.; Servent, V.; Bonneterre, J. Trastuzumab cardiac toxicity and HER2 polymorphism: A casecontrol
study. Cancer Res,  2010, 70, Abst P3-14-11.
[57] 
Stanton, S.E.; Ward, M.M.; Christos, P.; Sanford, R.; Lam, C.; Cobham, M.V.; Donovan, D.; Scheff, R.J.; Cigler, T.; Moore, A.; Vahdat, L.T.; Lane, M.E.; Chuang, E. Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity. BMC Cancer,  2015, 15, 267.
[58] 
Gómez Peña, C.; Dávila-Fajardo, C.L.; Martínez-González, L.J.; Carmona-Sáez, P.; Soto Pino, M.J.; Sánchez Ramos, J.; Moreno Escobar, E.; Blancas, I.; Fernández, J.J.; Fernández, D.; Correa, C.; Cabeza Barrera, J. Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients: a meta-analysis. Pharmacogenet. Genomics,  2015, 25, 388-393.
[59] 
Baselga, J.; Swain, S.M. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer,  2009, 9, 463-475.

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DOI https://dx.doi.org/10.2174/1568009618666171129222159	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576

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Toxicology of Trastuzumab: An Insight into Mechanisms of Cardiotoxicity

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