Oncogene (2007) 26, 6577–6592 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Targeting the function of the HER2 oncogene in human cancer therapeutics MM Moasser Department of Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA The year 2007 marks exactly two decades since human HER3 (erbB3) and HER4 (erbB4). The importance of epidermal growth factor receptor-2 (HER2) was func- HER2 in cancer was realized in the early 1980s when a tionally implicated in the pathogenesis of human breast mutationally activated form of its rodent homolog neu cancer (Slamon et al., 1987). This finding established the was identified in a search for oncogenes in a carcinogen- HER2 oncogene hypothesis for the development of some induced rat tumorigenesis model(Shih et al., 1981). Its human cancers. An abundance of experimental evidence human homologue, HER2 was simultaneously cloned compiled over the past two decades now solidly supports and found to be amplified in a breast cancer cell line the HER2 oncogene hypothesis. A direct consequence (King et al., 1985). The relevance of HER2 to human of this hypothesis was the promise that inhibitors of cancer was established when it was discovered that oncogenic HER2 would be highly effective treatments for approximately 25–30% of breast cancers have amplifi- HER2-driven cancers. This treatment hypothesis has led cation and overexpression of HER2 and these cancers to the development and widespread use of anti-HER2 have worse biologic behavior and prognosis (Slamon antibodies (trastuzumab) in clinical management resulting et al., 1989). This finding established the HER2 in significantly improved clinical antitumor efficacies that oncogene hypothesis that overexpression of HER2 is have transformed the clinical practice of oncology. In the etiologically linked with tumorigenesis in some human shadows of this irrefutable clinical success, scientific cancers. A substantialbody of experimentalevidence studies have not yet been able to mechanistically validate over the past two decades has come to solidly support that trastuzumab inhibits oncogenic HER2 function and it this hypothesis. In numerous in vitro and transgenic remains possible that the current clinical advances are a models, HER2 overexpression by itself is potently consequence of the oncogene hypothesis, but not a transforming. In addition, analysis of human breast translation of it. These looming scientific uncertainties cancers has shown that amplification of the HER2 locus suggest that the full promise of the treatment hypothesis is an early event in human carcinogenesis and along with may not yet have been realized. The coming decade will the experimentalevidence confirming its potently see a second generation of HER2-targeting agents transforming functions, this makes a highly compelling brought into clinical testing and a renewed attempt to case, implicating HER2 overexpression in the genesis of treat HER2-driven cancers through the inactivation of these human cancers. The signaling functions of HER2, HER2. Here, I review the development of treatments that the body of evidence confirming the transforming target HER2 in the context of the HER2 oncogene functions of HER2, the numerous proposed mechan- hypothesis, and where we stand with regards to the clinical isms mediating its transforming functions, and the data translation of the HER2 oncogene hypothesis. establishing the relevance of these findings to human Oncogene (2007) 26, 6577–6592; doi:10.1038/sj.onc.1210478; cancer pathogenesis were discussed in depth previously published online 7 May 2007 (Moasser, 2007). A direct consequence of the HER2 oncogene hypothesis of human cancer was that inhibi- Keywords: HER2; ErbB2; trastuzumab; herceptin; tors of oncogenic HER2 would be highly effective kinase inhibitor; breast cancer treatment for HER2-driven cancers. Here, I will review where we stand with regards to the testing of this treatment hypothesis and where we currently stand with regards to the therapeutic implications of the HER2 Introduction oncogene hypothesis. HER2 belongs to the human epidermal growth factor receptor (HER) family of tyrosine kinases consisting of Tumor dependence on HER2 EGFR (HER1, erbB1), HER2 (erbB2, HER2/neu), The tumorigenic potential of HER2 is solidly supported Correspondence: Dr MM Moasser, Department of Medicine, Com- by experimental models (Moasser, 2007). This by itself prehensive Cancer Center, University of California, San Francisco, proposes HER2 as a possible target for anti-cancer UCSF Box 0875, San Francisco, CA 94143-0875, USA, E-mail: [email protected] drugs. However, its suitability as a drug target is Received 15 March 2007; accepted 22 March 2007; published online 7 substantially strengthened by experiments demonstrat- May 2007 ing that HER2-driven tumors are dependent on HER2 HER2 oncogene in human cancer therapeutics MM Moasser 6578 function. This dependency, recently labeled oncogene pathways (Moody et al., 2005). Tetracycline-regulated addiction, identifies oncogenes that are high value NIH3T3-HER2 tumors cells that regress following targets for drug development (Weinstein, 2002). withdrawal of oncogene expression similarly recur following a period of remission despite absence of HER2-dependency of HER2-amplified human cancers oncogene expression, although the molecular features Experimentalmodelsof HER2-overexpressing cancer associated with HER2-independent recurrence in this cells using antisense, ribozyme or short interfering RNA modelare not yet described (Schiffer et al., 2003). The (siRNA) methodologies consistently show that HER2 direct relevance of these models of recurrence to human knockdown induces apoptosis in cell culture, or tumor tumors is not yet known and awaits analysis of human regression in vivo, in the absence of HER2 expression, tumors that have recurred following a complete remis- while tumor types that do not overexpress HER2 are not sion induced by HER2-targeted therapies. sensitive to HER2 knockdown (Colomer et al., 1994; Juhl et al., 1997; Roh et al., 2000; Choudhury et al., 2004; Faltus et al., 2004). Similar results are seen with Inhibition of HER2 for cancer therapy kinase-dead HER2 and intracellular single-chain anti- HER2 antibodies (Beerli et al., 1994; Messerle et al., The evidence to support the HER2 oncogene hypothesis 1994; Deshane et al., 1996). that HER2 initiates and drives the progression of HER2-overexpressing cancers is almost unimpeachable HER2-dependency in experimental models at this point. The direct consequence of this hypothesis Engineered models of HER2-driven transformation is the treatment hypothesis that inactivation of HER2 using tetracycline-inducible systems confirm that could be highly effective therapy for patients with HER2-induced tumors require HER2 for continued HER2-overexpressing cancers. Due to the large number tumorigenic growth and survival. This has been of patients with this type of cancer, testing of the HER2 demonstrated in an HER2-transformed NIH3T3 tumor treatment hypothesis has been one of the most actively model, wherein tumors regress upon withdrawal of the pursued programs in the cancer therapeutic arena. HER2 oncogene (Baasner et al., 1996; Schiffer et al., Testing in human subjects requires the development of 2003). This has also been corroborated in a tet-inducible safe and effective therapies that inactivate HER2 in transgenic models. Tetracycline-induced expression of patient tumors and in the best scenario are predicted to activated HER2 in squamous epithelia of mice results in produce complete remissions and recapitulate results severe hyperplastic abnormalities of squamous epithelial from preclinical models. Correlative scientific studies of tissues, which reverse upon withdrawalof the HER2 these therapeutic agents in preclinical models and in transgene expression (Xie et al., 1999). Tumors in patients are essentialto determine the validity of the MMTV-neuT mice are also dependent on continued treatment hypothesis. These efforts have led to the oncogene expression. In the MMTV-rtTA/TetO-NeuNT development of the anti-HER2 human monoclonal bitransgenic variant of this modelregulated by doxycy- antibody (mAb) trastuzumab, which has made signifi- cline, when expression of the neuT oncogene is induced cant clinical impact including a reduction in mortality in the mammary tissue of adult mice, the formation of from HER2-overexpressing disease. But mechanistic multiple mammary tumors and lung metastases is studies have been conflicting and suggest that the induced, and the entire primary tumor and metastatic treatment hypothesis may not yet have been effectively disease fully regresses when neuT expression is with- tested. If the treatment hypothesis is correct and drawn (Moody et al., 2002). inhibiting oncogenic HER2 function would result in Although each of these models is subject to criticisms complete tumor regression, the clinical impact is relating to their simplicity, when taken in aggregate, predicted to be much larger than currently realized they are highly consistent and collectively make a highly and we may have merely seen the tip of the iceberg. The compelling case that HER2-induced tumors are ad- available data with regards to several anti-HER2- dicted to HER2. This has made HER2 one of the most targeted therapies are reviewed below. The two modali- sought after targets in cancer drug development. ties for which there are considerable data are antibody therapies and small