Targeting HER3 for cancer treatment: a new horizon for an old target

Abstract

•HER3 is a tyrosine kinase receptor belonging to the HER family, ubiquitously expressed across different solid tumors.•HER3 has a role in tumorigenesis, disease progression, metastatic dissemination and anticancer drugs’ resistance.•Monoclonal antibodies and bispecific antibodies targeting HER3 have led to unsatisfactory results.•More promising results have been observed with novel ADCs, although burdened with hematologic and serious pulmonary toxicity•Biomarkers of response to HER3-directed agents need to be explored and prospectively validated. Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment. Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment. Human epidermal growth factor receptor 3 (HER3/ErbB3) is a tyrosine kinase receptor belonging to the HER family alongside epidermal growth factor receptor (EGFR; ErbB1 or HER1), HER2 (ErbB2), and HER4 (ErbB4).1Hynes N.E. MacDonald G. ErbB receptors and signaling pathways in cancer.Curr Opin Cell Biol. 2009; 21: 177-184Crossref PubMed Scopus (755) Google Scholar HER3 is a 180 kDa protein encoded by the ERBB3 gene on 12q13.2Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 86(23):9193-9197.Google Scholar Among the HER family members, HER3 is unique for different reasons. First, whereas EGFR binds several ligands and HER2 has none,3Burgess A.W. Cho H.-S. Eigenbrot C. et al.An open-and-shut case? recent insights into the activation of EGF/ErbB receptors.Mol Cell. 2003; 12: 541-552Abstract Full Text Full Text PDF PubMed Scopus (733) Google Scholar the preferential activators of HER3 are neuregulins (NRGs) 1-2,4Montero J.C. Rodríguez-Barrueco R. Ocaña A. Díaz-Rodríguez E. Esparís-Ogando A. Pandiella A. Neuregulins and cancer.Clin Cancer Res. 2008; 14: 3237-3241Crossref PubMed Scopus (92) Google Scholar also known as heregulins (HRG). Most importantly, HER3 has poor if no intracellular tyrosine kinase activity due to a divergence in critical residues in the intracellular kinase domain, which is locked in an inactive-like conformation, leading to a 1000-fold weaker kinase activity compared with EGFR.5Jura N. Shan Y. Cao X. Shaw D.E. Kuriyan J. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.Proc Natl Acad Sci USA. 2009; 106: 21608-21613Crossref PubMed Scopus (250) Google Scholar Nonetheless, HER3 is able to form heterodimers, preferentially with HER2 and/or EGFR, which dramatically enhance transphosphorylation and the consequent activation of mitogenic downstream pathways.6Alimandi M. Romano A. Curia M.C. et al.Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas.Oncogene. 1995; 10: 1813-1821PubMed Google Scholar Additionally, unlike other HER family members, HER3 dimerizes also with some non-HER receptors, namely mesenchymal-epithelial transition factor (MET) receptor and fibroblast growth factor receptor 2 (FGFR2).7Engelman J.A. Zejnullahu K. Mitsudomi T. et al.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science. 2007; 316: 1039-1043Crossref PubMed Scopus (3979) Google Scholar,8Kunii K. Davis L. Gorenstein J. et al.FGFR2 -amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival.Cancer Res. 2008; 68: 2340-2348Crossref PubMed Scopus (223) Google Scholar Furthermore, through a direct binding with the phosphoinositide-3 kinase (PI3K) p85 subunit, HER3 is a strong activator for PI3K/protein kinase B (AKT) signaling, pivotal for cancer survival.9Suenaga A. Takada N. Hatakeyama M. et al.Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides.J Biol Chem. 2005; 280: 1321-1326Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar HER3 also activates mitogen-activated protein kinase (MAPK) cascade, janus kinase (JAK) and proto-oncogene c-Src (SRC) signaling pathways, all involved in cancer proliferation10Liu J, Kern JA. Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol. 27(3):306-313.Google Scholar,11Huang X. Gao L. Wang S. et al.Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor in breast cancer cells resistant to herceptin.Cancer Res. 2010; 70: 1204-1214Crossref PubMed Scopus (183) Google Scholar (Figure 1). The role of HER3 in cancer biology is multifaceted. Ubiquitous HER3 expression is detected in various solid tumor types12Ocana A. Vera-Badillo F. Seruga B. Templeton A. Pandiella A. Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis.J Natl Cancer Inst. 2013; 105: 266-273Crossref PubMed Scopus (148) Google Scholar (Figure 2), with a proven role in disease progression. Two systematic analyses across multiple solid tumor types showed that HER3 expression was associated with worse overall survival, with a risk of death 1.60-fold higher compared with HER3-negative patients.12Ocana A. Vera-Badillo F. Seruga B. Templeton A. Pandiella A. Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis.J Natl Cancer Inst. 2013; 105: 266-273Crossref PubMed Scopus (148) Google Scholar,13Li Q. Zhang R. Yan H. et al.Prognostic significance of HER3 in patients with malignant solid tumors.Oncotarget. 2017; 8: 67140-67151Crossref PubMed Scopus (27) Google Scholar HER3 cooperates with other receptors not only to promote tumorigenesis and metastatic dissemination, but also to confer resistance to anticancer drugs. Preclinical data showed that HER3 contributes to HER2-mediated resistance to tamoxifen, and, consequently, reduction of expression of HER3 can reverse this resistance in breast cancer (BC) cell lines.14Liu B. Ordonez-Ercan D. Fan Z. Edgerton S.M. Yang X. Thor A.D. Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells.Int J Cancer. 2007; 120: 1874-1882Crossref PubMed Scopus (122) Google Scholar HER3 overexpression is also involved in resistance to fulvestrant: in BC cell lines, exposure to fulvestrant induced the expression and activity of HER3, significantly increasing cell proliferation compared with unexposed ones.15Hutcheson I.R. Goddard L. Barrow D. et al.Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1.Breast Cancer Res. 2011; 13: R29Crossref PubMed Scopus (36) Google Scholar HER3 confers resistance to HER2-targeted therapy too. Indeed, HER3 activates PI3K/AKT and SRC signaling pathways, two of the major molecular mechanisms involved in trastuzumab and lapatinib resistance, also through heterotrimers with HER2 and insulin-like growth factor-1 receptor (IGF-1R)11Huang X. Gao L. Wang S. et al.Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor in breast cancer cells resistant to herceptin.Cancer Res. 2010; 70: 1204-1214Crossref PubMed Scopus (183) Google Scholar,16Zhang S. Huang W.-C. Li P. et al.Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways.Nat Med. 2011; 17: 461-469Crossref PubMed Scopus (416) Google Scholar,17Chandarlapaty S. Sakr R.A. Giri D. et al.Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer.Clin Cancer Res. 2012; 18: 6784-6791Crossref PubMed Scopus (158) Google Scholar and HRG-driven HER3-EGFR-PI3K-PDK1 signaling axis.18Xia W. Petricoin E.F. Zhao S. et al.An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models.Breast Cancer Res. 2013; 15: R85Crossref PubMed Scopus (111) Google Scholar Lastly, HER3 is linked to resistance to chemotherapy: indeed, combined HER3 and EGFR overexpression worsen BC-specific and distant metastasis-free survival after adjuvant chemotherapy in triple-negative BC (TNBC).19Ogden A. Bhattarai S. Sahoo B. et al.Combined HER3-EGFR score in triple-negative breast cancer provides prognostic and predictive significance superior to individual biomarkers.Sci Rep. 2020; 10: 3009Crossref PubMed Scopus (18) Google Scholar Also, HER3 overexpression mediates paclitaxel resistance in HER2-overexpressing BC cell lines in a PI3K/AKT/mTOR signaling pathway-dependent fashion; once again, knocking down ErB3 expression can reverse this resistance mechanism.20Wang S. Huang X. Lee C.-K. Liu B. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin.Oncogene. 2010; 29: 4225-4236Crossref PubMed Scopus (106) Google Scholar Up-regulated HER3 signaling is involved in resistance to several other targeted therapies used for treating several tumor types, including anti-EGFR drugs gefitinib and cetuximab.21Erjala K. Sundvall M. Junttila T.T. et al.Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells.Clin Cancer Res. 2006; 12: 4103-4111Crossref PubMed Scopus (217) Google Scholar,22Yonesaka K. Zejnullahu K. Okamoto I. et al.Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.Sci Transl Med. 2011; 3 (99ra86)Crossref PubMed Scopus (497) Google Scholar One of the multiple genomic alterations known to be involved in acquired resistance to anti-EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated advanced non-small-cell lung cancer (aNSCLC) is HER3 up-regulation induced by osimertinib. Thus blocking HER3/EGFR dimerization is hypothesized to prevent or delay both acquired and primary resistance to EGFR inhibitors.23Romaniello D. Marrocco I. Belugali Nataraj N. et al.Targeting HER3, a catalytically defective receptor tyrosine kinase, prevents resistance of lung cancer to a third-generation EGFR kinase inhibitor.Cancers. 2020; 12: 2394Crossref PubMed Scopus (26) Google Scholar Moreover, MET amplification leads to gefitinib and erlotinib resistance via increased HER3/PI3K signaling.7Engelman J.A. Zejnullahu K. Mitsudomi T. et al.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science. 2007; 316: 1039-1043Crossref PubMed Scopus (3979) Google Scholar NRG1 and transcriptional HER3 activation are also involved in resistance to anaplastic lymphoma kinase (ALK) inhibitors and BRAF inhibitors, not only in NSCLC, but also in melanoma and thyroid cancer.24Wilson F.H. Johannessen C.M. Piccioni F. et al.A functional landscape of resistance to ALK inhibition in lung cancer.Cancer Cell. 2015; 27: 397-408Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 25Prasetyanti P.R. Capone E. Barcaroli D. et al.ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs).Oncotarget. 2015; 6: 16902-16911Crossref PubMed Scopus (30) Google Scholar, 26Abel E.V. Basile K.J. Kugel C.H. et al.Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3.J Clin Invest. 2013; 123: 2155-2168Crossref PubMed Scopus (202) Google Scholar Overall, there is a strong rationale behind the therapeutic targeting of HER3. Monoclonal antibodies (MoAbs) target HER3 by blocking the ligand binding or the heterodimerization of the receptors (Table 1; Figure 3A).27Jacob W. James I. Hasmann M. Weisser M. Clinical development of HER3-targeting monoclonal antibodies: Perils and progress.Cancer Treat Rev. 2018; 68: 111-123Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Several anti-HER3 MoAbs have been tested for therapeutic use in oncology and, despite a favorable toxicity profile in early clinical trials, objective responses were rarely observed, underscoring limited activity as single agents. Only three molecules demonstrated promising preliminary activity and progressed up to phase II and III clinical trials: patritumab (U3-1287), a fully human HER3-directed MoAb that binds to HRG and induces reduction of expression of HER3;28LoRusso P. Jänne P.A. Oliveira M. et al.Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors.Clin Cancer Res. 2013; 19: 3078-3087Crossref PubMed Scopus (74) Google Scholar seribantumab (MM-121), a fully human immunoglobulin G2 that inhibits HRG-mediated and downstream PI3K/AKT signaling;29Denlinger C.S. Keedy V.L. Moyo V. MacBeath G. Shapiro G.I. Phase 1 dose escalation study of seribantumab (MM-121), an anti-HER3 monoclonal antibody, in patients with advanced solid tumors.Invest New Drugs. 2021; 39: 1604-1612Crossref PubMed Scopus (9) Google Scholar lumretuzumab (RO5479599), an immunoconjugate containing a humanized HER3-directed MoAb that binds to HER3 extracellular domain, inhibiting HER3 dimerization and EGFR-dependent signaling, and activates the immune system to exert antibody-dependent cellular cytotoxicity.30Meulendijks D. Jacob W. Martinez-Garcia M. et al.First-in-human phase I study of lumretuzumab, a glycoengineered humanized anti-HER3 monoclonal antibody, in patients with metastatic or advanced HER3-positive solid tumors.Clin Cancer Res. 2016; 22: 877-885Crossref PubMed Scopus (51) Google ScholarTable 1HER3-targeted agents under clinical developmentDrug typeName of the compoundMechanism of actionPhase of clinical developmentSponsorMonoclonal antibodiesPatritumab (U3-1287)HER3-directed MoAbPhase IIIDaiichi Sankyo Co., LtdSeribantumab (MM-121)HER3-directed MoAbPhase IIElevation OncologyLumretuzumab (RO5479599)Immunoconjugate containing a glycoengineered, humanized HER3-directed MoAb; ADCCPhase MoAbPhase human HER3-directed MoAbPhase fully human HER3-directed Co., humanized HER3-directed MoAbPhase MoAbPhase MoAbPhase humanized MoAbPhase bispecific ADCCPhase antibody of humanized MoAbs EGFR, and HER3 bispecific bispecific Co., bispecific bispecific of an HER3-directed to the I inhibitor Sankyo Co., antibody-dependent cellular EGFR, epidermal growth factor human epidermal growth factor insulin-like growth factor-1 immunoglobulin monoclonal in a antibody-dependent cellular EGFR, epidermal growth factor human epidermal growth factor insulin-like growth factor-1 immunoglobulin monoclonal patients with metastatic BC a phase I study of and trastuzumab demonstrated and encouraging preliminary T. H. K. et al.Phase I study of HER3 targeted antibody patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer Clin 2015; Google Scholar a phase the of lumretuzumab to and paclitaxel in patients with HER3-positive to and in BC was burdened by a of and the therapeutic limited clinical A. J. et al.Phase study and clinical activity of the anti-HER3 antibody lumretuzumab combined with the antibody and paclitaxel in metastatic breast New Drugs. 2018; PubMed Scopus Google Scholar for the a phase II study of seribantumab in patients with receptor a clinical in the C. S. et al.A phase II of monoclonal antibody targeting or in with advanced or metastatic breast Clin Google Scholar The however, the phase II of seribantumab and fulvestrant in the phase II patritumab to erlotinib not survival in an of patients with and increased risk of J. J. M. et al.Phase 2 study of patritumab with erlotinib in advanced Clin PubMed Google Scholar was for HRG although a was not prospectively The phase III not the of patritumab and erlotinib in the of EGFR patients with HRG however, leading to the of the L. P. A. et patritumab erlotinib in EGFR advanced Cell Cancer a results of 2017; 12: Full Text Full Text PDF Google Scholar EGFR the of seribantumab to erlotinib to to a analysis a in patients with HRG et phase II of seribantumab in combination with in patients with EGFR cell lung PubMed Scopus (26) Google Scholar seribantumab for patients with Nonetheless, the role or HRG as a of response to seribantumab as the the phase II of seribantumab and in after to its primary of the phase II the combination of the anti-HER3 MoAb and in a of patients with head and neck squamous cell carcinoma activity was observed with an with the common et Phase II of in combination with in patients with advanced head and neck squamous cell carcinoma Clin Google Scholar a phase I study of in patients with advanced solid tumors, and the and the patients disease and response were B. S. et in a phase I study of a novel ErbB3 monoclonal antibody, in patients with advanced solid Full Text PDF Google Scholar the and resistance mechanisms to HER3-directed bispecific antibodies have been tested in clinical The promising bispecific is the that inhibits tumor growth and cells into the tumor demonstrated clinical activity in patients with NRG1 solid tumors, including and R. et Clinical of for a bispecific antibody in NRG1 Cancer Google et and of in advanced cancer and other solid NRG1 Clin 2021; PubMed Google Scholar and is under in the phase an bispecific to clinical compared with in in the phase II of NRG1 and was to be burdened by a of J. L. C. et phase II study of in squamous cell carcinoma of the head and neck 2016; 6: PubMed Scopus Google Scholar Moreover, the of to not clinical compared with in patients with metastatic et al.Phase II study of the inhibitor in combination with in metastatic cancer.Clin Cancer Res. 2018; PubMed Scopus Google Scholar The development of the bispecific MoAb was by the the results of the phase II as its to and not a clinical in patients with metastatic cancer with A. M. et phase II study of and and in metastatic 2018; 29: Full Text Full Text PDF Scopus Google Scholar The promising results have been observed with conjugates which for HER3-directed delivery of cytotoxic molecules to tumor of patritumab via a to a I inhibitor that inhibits and cell through cell and immune immune Y. K. Y. et al.A novel HER3-targeting therapeutic through the delivery of cytotoxic by Cancer Res. PubMed Scopus Google Scholar and in sensitizes cells for cell death protein 1 the of with immune inhibitors K. K. S. et sensitizes to by immune Clin Invest. Scopus Google Scholar 2 clinical on novel anti-HER3 clinical novel anti-HER3 or or not and HER3 with cell or or not not or metastatic or or or or metastatic dose or or or or or not breast EGFR, epidermal growth factor human epidermal growth factor head and neck squamous cell NSCLC, non-small-cell lung triple-negative breast in a breast EGFR, epidermal growth factor human epidermal growth factor head and neck squamous cell NSCLC, non-small-cell lung triple-negative breast The phase study in patients with promising and activity across all BC (Figure Overall, both of and 3 showed a toxicity profile and a of due to and Nonetheless, lung disease was observed in of 1 and 2 although was 3 or higher hematologic were observed the dose of and were by dose delay or and but in a N. T. et the phase study of patritumab a HER3-directed antibody-drug in patients with metastatic breast cancer Clin Google Scholar on encouraging was in the early the patients with BC a single dose of The primary was a in a combined score on tumor and that with P. T. J. et al.A predictive of response on tumor and in breast cancer with HER2 2018; 29: Full Text Full Text PDF PubMed Scopus Google Scholar led to with an of in the patients alongside increased immune and increased score in of were and and increased A. C. L. et in breast results of the Scholar The in patients with and the or in combination with therapy in Furthermore, the phase II in BC patients with HER3 expression after kinase the dose of a phase I an of in patients with EGFR-mutated progressed after and chemotherapy a of of response was with a of The common was in of patients with of although was to be not to study H. W.-C. et and of patritumab in cell lung cancer EGFR Clin Google Scholar on the phase II is in this whereas the phase III with in EGFR-mutated after of third-generation The combination of and is also under in a phase I clinical both in and also an of in a of patients with EGFR with and (Figure was of the of several other oncogenic including and ALK was the common and was observed in of the H. W.-C. et and of patritumab in cell lung cancer EGFR Clin Google Scholar to its kinase HER3 has been as a therapeutic Only a of its role and the with other ErbB receptors has an in the development of HER3-directed agents. MoAbs showed limited activity as single agents across several solid tumors. Nonetheless, promising results have been observed with the targeted delivery of cytotoxic payloads through the patritumab although hematologic and pulmonary require and of response to HER3-directed agents need to be explored and prospectively as the role of HRG expression

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