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Pertuzumab and Trastuzumab: the Rationale Way to Synergy

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Pertuzumab and Trastuzumab: the Rationale Way to Synergy Anais da Academia Brasileira de Ciências (2016) 88(1 Suppl.): 565-577 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201620150178 www.scielo.br/aabc Pertuzumab and trastuzumab: the rationale way to synergy SANDRINE RICHARD1, FRÉDÉRIC SELLE1, JEAN-PIERRE LOTZ1,2, AHMED KHALIL1, JOSEPH GLIGOROV1,2 and DANIELE G. SOARES1 1Medical Oncology Department, APREC (Alliance Pour la Recherche En Cancérologie), Tenon Hospital (Hôpitaux Universitaires de l’Est-Parisien, AP-HP), rue de la Chine, 75020 Paris, France 2Institut Universitaire de Cancérologie Université Pierre et Marie Curie (IUC-UPMC Univ Paris 06), Sorbonne Universités, 4 place Jussieu, 75005 Paris, France Manuscript received on March 13, 2015; accepted for publication on May 5, 2015 ABSTRACT It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthesizes preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action. Key words: breast cancer, dimerization, HER2/3, monoclonal antibody, pertuzumab, trastuzumab. INTRODUCTION By introducing trastuzumab (Herceptin) based therapy (Baselga et al. 1996) for the treatment The human epidermal growth factor receptor 2 of both, early (Slamon et al. 2011, Gianni et al. (HER2, ErbB-2 or HER-2/neu) gene, which encodes 2012) and metastatic HER2-positive breast cancer the HER2 receptor tyrosine kinase, is amplified in (Slamon et al. 2001), the prognosis of patients has about 20% of breast cancers (Ross and Fletcher substantially improved. 1998) and is associated with a poor prognosis and Trastuzumab works through multiple mecha- an aggressive phenotype (Slamon et al. 1987). nisms to inhibit tumor growth, including inhibition Correspondence to: Daniele Grazziotin-Soares of downstream signalling by blocking either HER2 E-mail: [email protected] homodimerization (Ghosh et al. 2011) or ligand- An Acad Bras Cienc (2016) 88 (1 Suppl.) 566 SANDRINE RICHARD et al. independent HER2/HER3 heterodime rization additional targets therapies for patients with (Junttila et al. 2009). Trastuzumab also inhibits trastuzumab-resistant breast cancer. A number of HER2 activation by inhibiting the cleava ge of its agents targeting various downstream components extracellular domain, thus preventing the formation of the pathways associated with HER2 signalling of the truncated and very active form of HER2, are currently under clinical investigation. These p95HER2 (Molina et al. 2001, Nahta and Esteva molecules include extracellular targeted therapies 2006). Finally, trastuzumab induces antibody- (monoclonal antibodies directed against HER dependent cell-mediated toxicity (Hudis 2007). family receptors), intracellular targeted therapies Despite its effectiveness in both adjuvant (tyrosine kinase inhibitors) and agents that target and metastatic settings, therapeutic resistance downstream effectors including members of either to trastuzumab remains an important clinical the mitogen-activated protein kinase (MAPK) or issue. Approximately, 15% of patients relapse the phosphatidylinositol 3-kinase (PI3K) pathways. after treatment (Kümler et al. 2014) because of In addition to PI3K/AKT modulators, targeted acquired resistance (Pohlmann et al. 2009, Chung therapies directed at the Hsp-90 apoptotic pathway et al. 2013). Indeed, median time to progression as well as factors modulating angiogenesis are also remained less than one year when trastuzumab was currently being developed (Rosen et al. 2010). combined with chemotherapy (Slamon et al. 2001, Esteva et al. 2002). THE EGFR FAMILY RECEPTORS It is important to mention that tumor cell HER2 is one of the four members of the human with acquired resistance to trastuzumab continues EGFR family, which also includes EGFR (HER1 to depend on the HER2 oncogene. Indeed, gene or ErbB-1), HER3, and HER4 (Hudis 2007). The amplification and RNA/protein overexpression are HER gene family is encoded by genes on different still present in trastuzumab-resistant HER2+ clones chromosomes and regulate normal breast growth (Ritter et al. 2007). The mechanisms underlying the frequent and development. However, their deregulations development of resistance to trastuzumab are leading to the activation of downstream pathways only starting to be understood and are still under appear to be particularly important, not only for active investigation (Garrett and Arteaga 2011). tumor development but also for treatment efficacy Several of the proposed mechanisms of resistance (Roskoski Jr 2004). to trastuzumab involve persistence or reactivation Each HER receptor shows an extracellular of the PI3K signalling through amplification of domain, a helical transmembrane segment, and an alternative tyrosine kinase receptor and/or mutations intracellular protein tyrosine kinase domain. The in the PI3K components (Rexer and Arteaga 2013). extracellular region of each HER receptor contains The formation of insulin-like growth factor-I four domains (I-IV). Domains I, III and IV are receptor (IGF-IR)/HER-2 heterodimer may also involved in ligand binding. The domain II loop, contribute to trastuzumab resistance (Nahta et al. the so called dimerization arm, promotes direct 2005). In particular, trastuzumab does not seem to receptor-receptor interaction. be able to prevent ligand-activated HER2/HER3 or Most of the HER receptors have a ligand. For HER2/HER1 heterodimerization which could give example, HER3 has a specific ligand, heregulin tumor cells a way to escape from the inhibitory (HRG), but does not have any kinase activity. effects of trastuzumab (Ghosh et al. 2011). HER2 is unique since it does not have any known The mechanism of HER2 signalling has been ligand (orphan receptor) but shows a tyrosine the focus of extensive research in order to identify kinase activity (Kim et al. 1998). HER2 is activated An Acad Bras Cienc (2016) 88 (1 Suppl.) PERTUZUMAB-TRASTUZUMAB COMBINATION 567 through homo- or heterotypic interactions of Preclinical works have reported that the its extracellular domain with that of other HER HER3-ligand binding HRG enhanced HER2/HER3 receptors (Arribas et al. 2011). heterodimer formation. Indeed, HRG induces re- In the absence of ligand binding, HER1 and cruitment of HER3 to an HER2-Src, resulting in HER3 exist in a tethered conformation in which upregulation of tyrosine phosphorylation and intramolecular interaction between domains II and kinase activation (Vadlamudi et al. 2003, Ghosh et IV blocks the function of dimerization domain al. 2011). In contrast to HER3/HER2 heterodimers, II. Ligand binding to HER receptors changes the HER2 homodimers and HER2/EGFR heterodimers tethered conformation into an extended confor- do not induce Src kinase phosphorylation and acti- mation, which exposes domain II, allowing them to vation (Vadlamudi et al. 2003, Huang et al. 2010). undergo dimerization (Hynes and Lane 2005, Gala It has been suggested that the formation of and Chandarlapaty 2014, Burgess et al. 2014). the HER2-HER3 heterodimer has the strongest Interestingly, the structure of the HER2 transforming capacity compared to the other HER extracellular region dramatically diverges from homo- and heterodimers. Despite the absence of those of either HER1 or HER3. The HER2 tyrosine kinase activity, HER3 has multiple PI3K extracellular region has indeed a fixed conformation docking sites on its cytoplasmic domain, which and the domain II loop is exposed to interactions therefore render it a potent activator of the tyrosine (Lemmon and Schlessinger 2010). This constitutive kinase enzyme (Xia et al. 2004). exposure of its dimerization arm might explain why HER2 is the favored partner for the other NOVEL STRATEGY TO TARGET HER2: PERTUZUMAB ligand-dependent HER (Graus-Porta et al. 1997, Yarden and Sliwkowski 2001, Badache and Hynes Pertuzumab is a recombinant, humanized, 2004). Moreover, the high level of HER2 present at monoclonal antibody that binds to the extracellular the surface of HER-positive tumor cells facilitates dimerization domain II of HER2 (located on the a spontaneous formation of HER2 homodimers opposite side of the domain IV where trastuzumab (Yarden and Sliwkowski 2001, Atalay et al. 2003). binds). Pertuzumab
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