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Targeting Human Epidermal Growth Factor Receptor 2: It Is Time to Kill Kinase Death Human Epidermal Growth Factor Receptor 3

Catalan Institute of Oncology, Health Services Division of Catalonia, Girona Biomedical Research Institute, Medical Oncology, Dr Josep Trueta University Hospital of Girona, Girona, Catalonia, Spain

Ruth Lupu

Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL

To the Editor:

Once again an inhibitor of the human epidermal growth factor receptor (HER) kinase family has been found to be useless in the management of human malignancies. de Bono et al¹ report that, consistent with the earlier experience of the anti-HER2 monoclonal antibody trastuzumab and the HER1 kinase inhibitors gefitinib and erlotinib, the second-generation anti-HER2 antibody pertuzumab as a single agent is ineffective in patients with hormone-refractory prostate cancer (HRPC).¹ In the very interesting editorial accompanying this study,² Solit and Rosen provide some insights that explain, at least in part, why HER kinase inhibitors have been so unsuccessful in HRPC. We would like to present other (up to date) factors that may have likely contributed to the failure of the pertuzumab regimen.

The inadequate target inhibition as a cause of pertuzumab failure in HRPC may not relate either to the dose levels studied or to the level of target inhibition required to induce tumoricidal effects in HRPC.² Rather, when one considers the ultimate mechanism of action of pertuzumab and that the process of ligand-induced HER receptors dimerization has a profound impact in the biologic activity of HER-targeted therapies, it is reasonable to suggest that pertuzumab was missing the target in the HRPC population studied by de Bono et al.¹ Recent publications describing the crystal structures of the extracellular region of each HER receptor in various ligand and therapeutic antibodies bound states have revealed that, although ligandless, the orphan HER2 receptor is the preferred dimerization partner for all the other HER receptors because it exhibits a fixed (constitutive) untethered dimerization-competent conformation that resembles the ligand-activated state of HER1 and HER3.^3-9 Pertuzumab binds this opened state of HER2 permanently poised for interaction with ligand-bound HER3 receptor, thus preventing autocrine or paracrine HER3 ligands from inducing HER2/HER3 transphosphorylated (active) heterodimers.^7-9 Therefore, pertuzumab cannot exhibit growth inhibition effects in low-level HER2-expressing tumors in the absence of HER3 ligand stimulation.^7-10 Patient stratification based, for instance, in the expression levels of the high-affinity combinatorial ligand for HER3 heregulin (HRG) in pretreatment samples might be extremely helpful in planning future pertuzumab-based clinical trials in HRPC. Supporting the key role of ligand-dependent HER3 transphosphorylation in the response to HER2-targeted inhibitors, we recently demonstrated that HER2-negative breast cancer cells engineered to constitutively exhibit an autocrine HRG/HER3 loop become exquisitely sensitive to the combination of trastuzumab with chemotherapy even in the absence of HER2 overexpression.^11,12 Supporting this notion, Schaefer et al¹³ recently showed that the growth-inhibiting effect of the pan-HER tyrosine kinase inhibitor (TKI) CI-1033 or PD158780 does not correlate with expression levels of HER1 or HER2 but rather with the autocrine presence of the HER3 ligand HRG.

Solit and Rosen suggest that the negative results of the anti-HER therapeutics gefitinib, erlotinib, trastuzumab, and pertuzumab in patients with prostate cancer may be an indication that HER2 overexpression does not have a primary pathogenic role in this disease.² Considering that responses to pertuzumab have been shown to correlate with HER2 activation in tumors without HER2 gene amplification,^10,14 it is more accurate to suggest that HER2 activation due to HER2 overexpression might play a critical role in early phases of prostate tumorigenesis whereas it might be of lesser importance in the biology of advanced HRPC. We and others have previously demonstrated that this is the case in breast cancer. ^15-19 Thus, a substantially greater frequency of HER2 phosphorylation (up to 58%) has been observed in HER2-overexpressing ductal carcinoma in situ whereas a HER2 active signaling occurs only in a minority of HER2-overexpressing invasive breast carcinomas (up to 12%), with only those bearing activated HER2 receptors displaying aggressive clinicopathologic features, adverse prognoses, and more importantly, better responses to anti-HER2 therapies such as trastuzumab. Therefore, even if assuming an incidence of HER2 overexpression of 20% to 50% in the HRPC population treated with pertuzumab, it should be expected that only few of these tumors will display a pertuzumab-sensitive HER2 phosphorylated (active) status. Studies in our laboratory recently revealed that, among 189 patients with invasive breast carcinoma, only seven (16%) of 45 HER2-phosphorylated tumors exhibited HER2 overexpression.¹¹ Conversely, 38 (67%) of 57 HER3 ligand HRG-overexpressing carcinomas showed an active (phosphorylated) status of HER2.¹¹ Phosphor-HER analyses, dual assays for HRG and HER2, or a triple test involving phosphor-HER2, HRG, and HER2 might be more useful than a single assay to identify patients likely to respond to pertuzumab.^11,12 Accordingly, we previously demonstrated that the antitumour actions expected from pharmacologic blockade of HER2/HER3 dimer can be entirely mimicked by specifically blocking the autocrine expression of the HER3 ligand HRG in the absence of HER2 gene amplification, further supporting the notion of ligand-bound HER3 receptor as a commonly forgotten player capable to dictate cancer cell responses to HER-targeted inhibitors.²⁰

de Bono et al suggest that the negative results of their study may indicate that the antitumor activity is abrogated by activation of other functional HER receptor dimmers (eg, HER1-HER1, and HER1-HER3).¹ Indeed, pertuzumab target itself (ie, the HER2/HER3 heterodimer) may autoregulate its escape. Based on the fact that kinase defective HER3 can be phosphorylated by HER1 or HER2 and that HER3 can couple to the prosurvival phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway directly, whereas HER1 and HER2 cannot, Sergina et al have recently demonstrated that HER3 and consequently PI3K/Akt pathway evade inhibition by current HER family TKIs due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium.²¹ In their hands, an Akt-mediated negative feedback signaling appears to promote increased membrane HER3 (driving the phosphorylation reaction) and reduced HER3 phosphatase activity (impeding the dephosphorylation reaction). Thus, although HER3 is not a direct target of HER1/2 monoclonal antibodies and TKIs, HER3 substrate resistance ultimately determines their efficacy because HER3 signaling is buffered against an incomplete inhibition of HER2 kinase. Regardless the ultimate upregulatory mechanism (ie, genetic loss of PTEN function² and/or reactivation of HER3 on pharmacologic blockade of the HER network²¹), it appears that antiapoptotic PI3K/Akt signaling will be constitutively active in a majority of HER2-driven tumors. Therefore, the identification of HER2-positive patients likely to respond or escape HER-targeted therapies will require the incorporation of markers such as HER3 transactivation, HER2/HER3 dimer, or others that may inform the level of HER2 engagement, including the activation status of downstream transduction cascades.

It is unclear at this time how to select a cancer patient population most likely to be sensitive to HER inhibitors. Although neither (kinase death) HER3 nor orphan HER2 can be activated by HER-related ligands on their own, the formation of HER2/HER3 heterodimers creates the most mitogenic and transforming receptor complex within the HER (erbB) family of transmembrane receptor tyrosine kinases.²² We are now accumulating evidence suggesting that the biologic marker with which to assess the efficacy of HER-targeted therapies should be transphosphorylation of HER3 rather than autophosphorylation of HER1 and/or HER2.²¹ Certainly, regardless the mechanism triggering the formation of HER3/HER2 heterodimers (ie, HER2 overexpression or overall low HER2 but high levels of the HER3 ligand HRG), it appears that cancer cells restore the impaired tyrosine kinase activity of the otherwise catalytically inactive HER3 to respond against any disturbance in the oncogenic function of the HER receptor tyrosine kinase network (Fig 1). Perhaps it is time to kill kinase death HER3 if we want to successfully manage HER2-driven human cancer.

View larger version (34K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cancer cells restore the impaired tyrosine kinase (TK) activity of the otherwise catalytically inactive human epidermal growth factor receptor (HER) 3 to respond against any disturbance in the oncogenic function of the HER receptor tyrosine kinase network. The incorporation of markers such as HER3 transactivation, HER2/HER3 dimer, or others that may inform the level of HER pathway engagement (eg, phosphatidylinositol-3-OH kinase [PI3K]/Akt pathway) may allow the identification of patients likely to respond or escape HER-targeted therapies. MAb, monoclonal antibody; TKI, tyrosine kinase inhibitor; HRG, heregulin; ECM, extracellular milieu; Cyt, cytoplasm; PTEN, Phosphatase and Tensin homolog deleted on chromosome 10; Akt, protein kinase B.

The author(s) indicated no potential conflicts of interest.

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