Activation Of HER Receptors Research Articles

Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models

BackgroundPrevious studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear.MethodsWe investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays.ResultsCompared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab.ConclusionThis study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.

HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer.

Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.

Abstract 328: ADAM17-induced activation of HER receptors mediate resistance to trastuzumab in a subset of moderate HER2-expressing breast cancer cells

Abstract Currently anti-HER2 therapies are indicated for HER2-positive breast cancer patients that are IHC3+ or FISH positive. However, there have been studies suggesting that some HER2-negative patients may also respond to these treatments. Previously, our laboratory showed that trastuzumab upregulates ADAM17 and ADAM10 levels; and the resultant ligand release and the activation of HER receptors mediates trastuzumab acquired resistance in HER2-positive breast cancer. The aim of this study is to further understand the mechanisms of response and resistance of HER2 targeting agents such as trastuzumab and neratinib in low and moderate HER2-expressing breast cancer cells. The HER2 expression of a panel of eight breast cell lines was assessed by IHC, FISH, western blot, and qRT-PCR. Using cell viability studies we found that in comparison with high (IHC 3+) and low HER2 expressing (IHC 0 or 1+) breast cancer cells, moderately expressing HER2 (2+) cells showed an intermediate response to trastuzumab and neratinib. Three moderate HER2-expressing breast cancer cell lines (IHC 2+), MDA-MB-361, MDA-MB-453 and HCC1569 were shown to respond to increasing doses of neratinib (with an IC50 less than 30nM). However, increasing doses of trastuzumab (up to 120 μg/ml) was unable to decrease the cell viability of these cells to below 50% of the control. The response to trastuzumab and neratinib correlated with basal ADAM17 but not ADAM10 expression. Trastuzumab treatment led to an upregulation of ADAM17 and the shedding of HER ligands in the media, as well as the phosphorylation of HER members. ADAM17 inhibition, using a specific anti-ADAM17 antibody or knockdown of the protein, decreased activation of HER members as well as downstream markers, correlating with reduced cell viability in moderate HER2-expressing cell lines. In addition, the combination of trastuzumab with neratinib was more effective than either single agent in moderate HER2-expressing cell lines. Thus, ADAM17 may play a key role in the resistance to trastuzumab in moderate HER2-expressing breast cancer cells. Combining trastuzumab with an ADAM17 inhibitor or an irreversible pan-HER inhibitor such as neratinib may be an effective therapeutic strategy for targeting breast cancers with moderate HER2 expressing tumors. Citation Format: Katharina Feldinger, Vasanthy Vigneswara, Gillian Murphy, Anthony Kong. ADAM17-induced activation of HER receptors mediate resistance to trastuzumab in a subset of moderate HER2-expressing breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 328.

Regulation of the prometastatic neuregulin-MMP13 axis by SRC family kinases: therapeutic implications.

Metastatic dissemination of tumor cells is responsible for the fatal outcome of breast cancer. Therefore, understanding the mechanisms involved in dissemination is essential for the development of new therapeutic strategies to prevent metastasis. One mechanism involved in metastatic dissemination of breast cancer cells is dependent on control of the production of matrix metalloproteinases by the neuregulins (NRGs). The NRGs are polypeptide factors that act by binding to the ErbB/HER subfamily of receptor tyrosine kinases. NRG‐mediated activation of HER receptors causes an increase in the production of metalloprotease 13 (MMP13, also termed collagenase‐3), which facilitates metastatic dissemination of breast tumors. In this context, we aimed to explore whether the clinically approved tyrosine kinase inhibitor dasatinib was able to neutralize this mechanism of metastatic dissemination. Here, we show that dasatinib restricted NRG‐induced MMP13 upregulation, both in vitro and in vivo, and in vivo metastatic dissemination of breast cancer cells. Chemical proteomics studies showed that the main cellular targets of dasatinib were SRC family kinases (SFKs). Moreover, genetic studies showed that knockdown of SRC or YES strongly inhibited NRG‐induced MMP13 upregulation in vitro. Mechanistically, dasatinib treatment or knockdown of SRC also inhibited ERK1/2 kinases in vitro, which were required for NRG‐induced MMP13 upregulation. These results open the possibility of clinically exploring the antitumoral action of dasatinib in those tumors in which the NRG–MMP13 signaling axis may play a relevant role in the control of tumor cell dissemination.

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells.

Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.

Deciphering the stepwise binding mode of HRG1β to HER3 by surface plasmon resonance and interaction map.

For the development of efficient anti-cancer therapeutics against the HER receptor family it is indispensable to understand the mechanistic model of the HER receptor activation upon ligand binding. Due to its high complexity the binding mode of Heregulin 1 beta (HRG1β) with its receptor HER3 is so far not understood. Analysis of the interaction of HRG1β with surface immobilized HER3 extracellular domain by time-resolved Surface Plasmon Resonance (SPR) was so far not interpretable using any regular analysis method as the interaction was highly complex. Here, we show that Interaction Map (IM) made it possible to shed light on this interaction. IM allowed deciphering the rate limiting kinetic contributions from complex SPR sensorgrams and thereby enabling the extraction of discrete kinetic rate components from the apparently heterogeneous interactions. We could resolve details from the complex avidity-driven binding mode of HRG1β with HER3 by using a combination of SPR and IM data. Our findings contribute to the general understanding that a major conformational change of HER3 during its activation is induced by a complex sequential HRG1β docking mode.

Targeting HER Receptors in Cancer

Receptor tyrosine kinases play important roles in animal development and their deregulation has been linked to several pathologies, including cancer or diabetes. In cancer, the ERBB/HER family of receptors has been shown to participate in the pathophysiology of breast, gastric, colorectal, lung and head and neck tumors. Activation of HER receptors occurs by receptor-receptor interactions facilitated by ligand binding, overexpression or molecular alterations of the HER receptors. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this review, we will describe the biological bases that govern HER receptor activation, and this will represent the bases for the explanation of how to target HER receptors in cancer. We will discuss the current therapeutic options to target HER receptors, which are based on anti-receptor antibodies or small molecule kinase inhibitors. We will also describe current clinical applications and future developments of agents which target HER receptors. Finally, we will mention mechanism of resistance to anti-HER therapies, and will describe options to overcome such resistances.

Targeting HER Receptors in Cancer

Receptor tyrosine kinases play important roles in animal development and their deregulation has been linked to several pathologies, including cancer or diabetes. In cancer, the ERBB/HER family of receptors has been shown to participate in the pathophysiology of breast, gastric, colorectal, lung and head and neck tumors. Activation of HER receptors occurs by receptor-receptor interactions facilitated by ligand binding, overexpression or molecular alterations of the HER receptors. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this review, we will describe the biological bases that govern HER receptor activation, and this will represent the bases for the explanation of how to target HER receptors in cancer. We will discuss the current therapeutic options to target HER receptors, which are based on anti-receptor antibodies or small molecule kinase inhibitors. We will also describe current clinical applications and future developments of agents which target HER receptors. Finally, we will mention mechanism of resistance to anti-HER therapies, and will describe options to overcome such resistances. Keywords: HER receptors, kinase inhibitors, EGF ligands, targeted therapies, deregulation, cancer, diabetes, tumors, anti-receptor antibodies, resistances

Targeting HER Receptors in Cancer

Receptor tyrosine kinases play important roles in animal development and their deregulation has been linked to several pathologies, including cancer or diabetes. In cancer, the ERBB/HER family of receptors has been shown to participate in the pathophysiology of breast, gastric, colorectal, lung and head and neck tumors. Activation of HER receptors occurs by receptor-receptor interactions facilitated by ligand binding, overexpression or molecular alterations of the HER receptors. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this review, we will describe the biological bases that govern HER receptor activation, and this will represent the bases for the explanation of how to target HER receptors in cancer. We will discuss the current therapeutic options to target HER receptors, which are based on anti-receptor antibodies or small molecule kinase inhibitors. We will also describe current clinical applications and future developments of agents which target HER receptors. Finally, we will mention mechanism of resistance to anti-HER therapies, and will describe options to overcome such resistances. Keywords: HER receptors, kinase inhibitors, EGF ligands, targeted therapies, deregulation, cancer, diabetes, tumors, anti-receptor antibodies, resistances

86P The Role of Adam17 in Her2 Moderately Expressing Breast Cancer

ABSTRACT Trastuzumab has been shown to increase the survival of HER2 positive breast cancer (HER2 3+) patients and some clinical trials revealed that patients with moderately expressed HER2 (HER2 2+) breast cancer may also respond. However, there is a need to further understand the mechanisms of resistance to trastuzumab and to explore other targeted therapies. Members of a disintegrin and metalloproteases (ADAMs) are responsible for shedding of a variety of ErbB ligands. The most important members are ADAM10 and ADAM17 and we investigated the role of these ADAMs in trastuzumab treatment and resistance in HER2 2+ breast cancer cell lines. We first assessed the effect of trastuzumab on MDA-MB-453 and MDA-MB-361 cells and confirmed that those are less sensitive than HER2 positive SKBR3 cells but respond better than MCF7 cells. We found that trastuzumab treatment does not decrease pHER2 in HER2 2+ expressing cells. We previously showed that ADAM17 mediated heregulin release maintains HER2 phosphorylation in HER2 3+ breast cancer cells. Therefore we proceeded to investigate the levels of ADAM17 and heregulin and found an increase of both in HER2 2+ cells in comparison to SKBR3 cells. Interestingly, the use of a specific anti ADAM17 antibody leads to a decrease of pPKB as well as pHER3 and pHER2 in MDA-MB-453 cells. Strikingly, in cell viability studies monotherapy with an anti ADAM17 antibody had a significant effect in reducing cell proliferation of these cells and an additive effect in trastuzumab treatment. Furthermore, ADAM10 inhibition had only little effects, indicating that these cells may rely on HER3 activation through heregulin release by ADAM17. Thus, ADAM17 may play a key role in trastuzumab resistance in HER2 moderately expressing breast cancer cells. Our results suggest that in those cells, ADAM17 results in HER ligand sheddase which in turn may lead to the activation of HER receptors and the maintenance of pHER2. We demonstrated that an anti ADAM17 antibody is able to decrease pHER2, pHER3, as well as pPKB and is effective as monotherapy and additive to trastuzumab treatment in HER2 2+ breast cancer cells. We recommend that inhibition of ADAM17 with or without trastuzumab should be considered as a potential targeted therapy strategy in HER2 2+ breast cancer patients. Disclosure G. Murphy: The anti ADAM17 antibody was developed by Prof. Murphy's laboratory. Please see: Tape et al. Cross-domain inhibition of TACE ectodomain. Proc Natl Acad Sci USA 2011; 108(14):5578-83. All other authors have declared no conflicts of interest.

Abstract 5362: The role of adam10 in trastuzumab resistance of her2 positive breast cancer cell lines

Abstract Members of a disintegrin and metalloproteases (ADAMs) are responsible for shedding of a variety of ErbB ligands. One of them, ADAM10, has been shown to cleave several pro-ligands, including betacellulin and HB-EGF. ADAM10 further may play a role in trastuzumab resistance since it is also responsible for HER2 shedding, thereby removing the binding site for trastuzumab. It was reported that ADAM10 inhibitor INCB 7839 could reduce HER2 cleavage in patients with HER2 positive breast cancer. However, a direct correlation of trastuzumab treatment and ADAM10 and the precise role of ADAM10 in trastuzumab resistance have not been elucidated. The aim of this project is therefore to investigate the role of ADAM10 in trastuzumab treatment and resistance in HER2 positive breast cancer cell lines. Using western blot, we showed that one hour of trastuzumab treatment leads to an upregulation of ADAM10 in conditioned medium and cell lysates of BT474 cells, which was correlated with an elevated level of betacellulin. Additionally, the use of a specific ADAM10 inhibitor in turn leads to downregulation of betacellulin levels in culture medium. Whereas one hour of trastuzumab treatment could not decrease pHER2, its combination with ADAM10 inhibitor reduced pHER2 level. To further investigate the role of ADAM10 in relation to trastuzumab treatment, we used cell viability studies to assess the effect of a specific ADAM10 inhibitor with or without trastuzumab treatment. Although monotherapy with ADAM10 inhibitor only had minimal influence, combining it with trastuzumab significantly enhanced trastuzumab in reducing cell proliferation of BT474 cells. Interestingly, the addition of ADAM10 inhibitor to trastuzumab exerts an even greater inhibition of cell proliferation in the BT474 trastuzumab resistant cell line. Since the N-domain of ADAM10 was shown to be cleaved by ADAM9 in other cell lines, we also assessed ADAM9 level in response to trastuzumab treatment. In BT474 lysates, ADAM9 level was increased after one hour of treatment, correlating with increased ADAM10 level in the medium. ADAM9 level was also found to be increased in the trastuzumab-resistant HER2 positive cell line in comparison to the sensitive cell line. Thus, ADAM10 as well as ADAM9 may play a key role in trastuzumab resistance in HER2 positive breast cancer cells. Our results suggest that the increased level of ADAM10 results in HER ligand sheddase which in turn may lead to the activation of HER receptors and the maintenance of pHER2. We demonstrated that ADAM10 inhibitor in combination with trastuzumab is able to decrease pHER2 and potentiate the trastuzumab effect in HER2 positive breast cancer cells. The role of ADAM9 in its regulation of ADAM10 in relation to trastuzumab treatment is currently under investigation. We recommend that inhibition of ADAM10 should be considered as a potential strategy to improve trastuzumab response in HER2 positive breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5362. doi:10.1158/1538-7445.AM2011-5362

HER2 Oncogenic Function Escapes EGFR Tyrosine Kinase Inhibitors via Activation of Alternative HER Receptors in Breast Cancer Cells

BackgroundThe response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses.Methodology and Principal FindingsHere we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both Förster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment–induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa.Conclusions and SignificanceThese results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients.

HER receptor signaling confers resistance to IGF-1R targeted therapy

14510 Background: Signaling through the insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the resistance to a number of clinically relevant anti-cancer agents, including inhibitors of the HER family of receptors. Preliminary data suggests that co-inhibition of IGF and HER pathways may improve the efficacy of targeting these pathways individually. Methods: Five ovarian cancer cell line where treated with the IGF-1R inhibitor, BMS-536924 (924) and/or the panHER inhibitor, BMS-599626. Activity was assessed by proliferation and apoptotic assays. Protein expression/activation was assessed by western blotting. Stably transfected MCF-7 variants were generated to contain either the empty expression vector (M/-), EGFR/HER1 (M/H1) or HER2 (M/H2). MCF-7R4 cells (R4) are a clonal isolate of MCF-7 cells passaged in high concentration of the IGF-1R inhibitor, BMS-554417. The expression profile of R4 cells were compared to MCF-7 using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Results: IGF-1R and HER receptor co-inhibition had synergistic anti- proliferative activity in all 5 ovarian cell lines investigated. The mechanism of this synergy was enhancement of apoptosis. Evidence of HER receptor activation was observed in all cell lines in response to IGF-1R inhibition. M/H1 and M/H2 became highly resistant to the effects of 924 in the presence of EGF and heregulin, respectively. R4 cells are cross-resistant to 924 and other IGF-1R inhibitors. Compared to MCF-7 cells, HER2 and HER3 are upregulated and overactivated in R4 cells. Additionally, R4 cells have altered expression of IGFBP-5, -6 and IRS-1, -2. Conclusions: Co-inhibition of IGF-1R and HER receptors leads to synergistic activity in all tested ovarian cancer cell lines, all of which exhibited evidence of crosstalk. Activated EGFR or HER2 appears sufficient for resistance to IGF-1R inhibition. As IGF-1R inhibition strategies enter the clinic, HER receptors status and consideration of co-inhibition will be important for their development. Several IGF-1 system related proteins, including IGFBP-5 and 6 may have utility in predicting response to IGF-1R targeted therapy. Supported by the ASCO Young Investigator Award, Mayo Clinic Breast SPORE (CA116201–01) and K12 program (CA090628–05). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, Pfizer Oncology Bristol-Myers Squibb

Improved antitumor therapy by dual targeting of estrogen and growth factor receptor signaling in human breast cancer cells

637 Background: Breast cancer growth is tightly regulated by interactions between growth factor and estrogen receptors. Dimerization is crucial for activation of HER receptors (EGFR, HER2, HER3, HER4) that contribute to modulation of tumor progression and the failure of antiestrogen therapy. HER2 is the preferred dimerization partner in a process stimulated by the several HER receptor ligands. HER2 antibody (trastuzumab) shows antitumor efficacy in HER2-overexpressing cancers. New antibodies that disrupt HER2 dimerization (pertuzumab) may be useful in treating cancers with normal HER2 levels. Methods: Estrogen receptor (ER)-positive tumor cells with normal HER levels (MCF-7, ZR75), as well as cells engineered for HER2-overexpression (MCF-7/HER2, ZR75/HER2) or tamoxifen resistance (MCF-7/TAM), were grown in vitro and as xenografts in nude mice and treated with tamoxifen, fulvestrant (Faslodex), trastuzumab or pertuzumab, alone or combined. Effects of agents on phosphorylation of ER and coactivator AIB1, ER-dependent transcripts, p27 and VEGF secretion were assessed. Results: Growth of ER-positive tumors with low HER is reduced by tamoxifen and fulvestrant. In contrast, HER2-overexpressing tumors are tamoxifen-resistant but retain sensitivity to fulvestrant and show greater, synergistic antitumor effects with trastuzumab-fulvestrant combined. Similarly, non-HER2-overexpressing tumors with or without tamoxifen resistance are sensitive to fulvestrant, but fulvestrant-pertuzumab elicits more profound antitumor effects (P&lt;0.001). Enhanced inhibitory action of fulvestrant-pertuzumab is related, in part, to changes in phosphorylation of ER and AIB1, leading to blockade of ER-induced transcripts, as well as nuclear localization of p27, a CDK-inhibitor that downregulates cell proliferation. Further, enhanced tumor secretion of VEGF after estrogen and HER signaling is markedly reduced by fulvestrant-pertuzumab as compared with either agent alone (P&lt;0.001). Conclusions: Pertuzumab promotes antitumor efficacy of the pure antiestrogen, fulvestrant, and dual disruption of ER and HER signaling may be a new way to optimize hormonal therapy and overcome antiestrogen resistance. Supported by US Army BCRP and Stiles Program. [Table: see text]

The HER receptor family: a rich target for therapeutic development

PurposeThe key role of the HER family of receptors in cancer has been widely acknowledged. HER receptor activation occurs via ligand binding or nonligand-dependent receptor dimerization, initiating signals that promote tumorigenesis via cell proliferation, survival, migration, adhesion, and differentiation. Therapeutic strategies designed to target and inhibit HER activation that are in clinical development are reviewed, including examples of both small-molecule tyrosine kinase inhibitors and monoclonal antibodies. Materials and methodsA literature review. ResultsTarceva is a potent, highly selective, reversible inhibitor of HER1/epidermal growth factor receptor tyrosine kinase with inhibitory activity against various in vitro and in vivo models of solid human tumors. Phase II trials in refractory non–small-cell lung, head-and-neck, and ovarian cancer have demonstrated clinical activity, including objective responses and prolonged, stable disease. Four Phase III trials are ongoing evaluating primarily the effect on survival of Tarceva in combination with chemotherapy. 2C4 is a humanized anti-HER2 monoclonal antibody that binds to a broad, extracellular epitope, resulting in steric inhibition of HER–receptor complex formation that involves HER2. 2C4 has shown significant activity in xenograft models of prostate, lung, and breast cancer. 2C4's activity, unlike Herceptin's, is not dependent on HER2 amplification. This antibody is in early clinical development. ConclusionThe strategy of targeting the HER system has been further validated by early experience with Tarceva and 2C4. The optimal clinical benefit of these agents will likely involve combinations of biologic agents, with or without traditional chemotherapy, and will be guided by critical predictive diagnostic information.