HER3 signaling and targeted therapy in cancer

  • Rosalin Mishra | mishrarn@ucmail.uc.edu James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States. http://orcid.org/0000-0002-9808-8797
  • Hima Patel James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States.
  • Samar Alanazi James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States.
  • Long Yuan James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States.
  • Joan T. Garrett James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States.


ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.



PlumX Metrics


Download data is not yet available.


Hynes, N.E.a. and G. MacDonald, ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol, 2009. 21(2): p. 177-84. DOI: https://doi.org/10.1016/j.ceb.2008.12.010

Olayioye, M.A., et al., The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J, 2000. 19(13): p. 3159-67. DOI: https://doi.org/10.1093/emboj/19.13.3159

Cho, H.S., et al., Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature, 2003. 421(6924): p. 756-60. DOI: https://doi.org/10.1038/nature01392

Riese, D.J., 2nd and D.F. Stern, Specificity within the EGF family/ErbB receptor family signaling network. Bioessays, 1998. 20(1): p. 41-8. DOI: https://doi.org/10.1002/(SICI)1521-1878(199801)20:1<41::AID-BIES7>3.0.CO;2-V

Yarden, Y. and M.X. Sliwkowski, Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2001. 2(2): p. 127-37. DOI: https://doi.org/10.1038/35052073

Baselga, J. and S.M. Swain, Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer, 2009. 9(7): p. 463-75. DOI: https://doi.org/10.1038/nrc2656

Amin, D.N., M.R. Campbell, and M.M. Moasser, The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol, 2010. 21(9): p. 944-50. DOI: https://doi.org/10.1016/j.semcdb.2010.08.007

Junttila, T.T., et al., Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell, 2009. 15(5): p. 429-40. DOI: https://doi.org/10.1016/j.ccr.2009.03.020

Kraus, M.H., et al., 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, 1989. 86(23): p. 9193-7. DOI: https://doi.org/10.1073/pnas.86.23.9193

Plowman, G.D., et al., Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci U S A, 1990. 87(13): p. 4905-9. DOI: https://doi.org/10.1073/pnas.87.13.4905

Tanner, B., et al., ErbB-3 predicts survival in ovarian cancer. J Clin Oncol, 2006. 24(26): p. 4317-23. DOI: https://doi.org/10.1200/JCO.2005.04.8397

Lipton, A., et al., HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat, 2013. 141(1): p. 43-53. DOI: https://doi.org/10.1007/s10549-013-2665-0

Koumakpayi, I.H., et al., Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res, 2006. 12(9): p. 2730-7. DOI: https://doi.org/10.1158/1078-0432.CCR-05-2242

Hayashi, M., et al., High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res, 2008. 14(23): p. 7843-9. DOI: https://doi.org/10.1158/1078-0432.CCR-08-1064

Nielsen, T.O., et al., Co-expression of HER3 and MUC1 is associated with a favourable prognosis in patients with bladder cancer. BJU Int, 2015. 115(1): p. 163-5. DOI: https://doi.org/10.1111/bju.12658

Siegfried, J.M., et al., Expression of PAM50 genes in lung cancer: evidence that interactions between hormone receptors and HER2/HER3 contribute to poor outcome. Neoplasia, 2015. 17(11): p. 817-25. DOI: https://doi.org/10.1016/j.neo.2015.11.002

Reschke, M., et al., HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res, 2008. 14(16): p. 5188-97. DOI: https://doi.org/10.1158/1078-0432.CCR-08-0186

Beji, A., et al., Toward the prognostic significance and therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer. Clin Cancer Res, 2012. 18(4): p. 956-68. DOI: https://doi.org/10.1158/1078-0432.CCR-11-1186

Qian, G., et al., Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma. Cancer, 2015. 121(20): p. 3600-11. DOI: https://doi.org/10.1002/cncr.29549

Liles, J.S., et al., ErbB3 expression promotes tumorigenesis in pancreatic adenocarcinoma. Cancer Biol Ther, 2010. 10(6): p. 555-63. DOI: https://doi.org/10.4161/cbt.10.6.12532

Travis, A., et al., C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer, 1996. 74(2): p. 229-33. DOI: https://doi.org/10.1038/bjc.1996.342

Siegel, P.M., et al., Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J, 1999. 18(8): p. 2149-64. DOI: https://doi.org/10.1093/emboj/18.8.2149

Servidei, T., et al., Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib. Int J Cancer, 2008. 123(12): p. 2939-49. DOI: https://doi.org/10.1002/ijc.23902

Lee-Hoeflich, S.T., et al., A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res, 2008. 68(14): p. 5878-87. DOI: https://doi.org/10.1158/0008-5472.CAN-08-0380

Vaught, D.B., et al., HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res, 2012. 72(10): p. 2672-82. DOI: https://doi.org/10.1158/0008-5472.CAN-11-3594

Garrett, J.T., et al., Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A, 2011. 108(12): p. 5021-6. DOI: https://doi.org/10.1073/pnas.1016140108

Chandarlapaty, S., et al., AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell, 2011. 19(1): p. 58-71. DOI: https://doi.org/10.1016/j.ccr.2010.10.031

Fujiwara, S., et al., Association of ErbB1-4 expression in invasive breast cancer with clinicopathological characteristics and prognosis. Breast Cancer, 2014. 21(4): p. 472-81. DOI: https://doi.org/10.1007/s12282-012-0415-5

Morrison, M.M., et al., ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest, 2013. 123(10): p. 4329-43. DOI: https://doi.org/10.1172/JCI66764

Balko, J.M., et al., The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci U S A, 2012. 109(1): p. 221-6. DOI: https://doi.org/10.1073/pnas.1115802109

Curley, M.D., et al., Seribantumab, an anti-ERBB3 Antibody, delays the onset of resistance and restores sensitivity to letrozole in an estrogen receptor-positive breast cancer model. Mol Cancer Ther, 2015. 14(11): p. 2642-52. DOI: https://doi.org/10.1158/1535-7163.MCT-15-0169

Collins, D., et al., Direct estrogen receptor (ER) / HER family crosstalk mediating sensitivity to lumretuzumab and pertuzumab in ER+ breast cancer. PLoS One, 2017. 12(5): p. e0177331. DOI: https://doi.org/10.1371/journal.pone.0177331

Mishra, R., et al. Genomic alterations of ERBB receptors in cancer: clinical implications.Oncotarget, 2017. 8(69): p. 114371-114392. DOI: https://doi.org/10.18632/oncotarget.22825

Jaiswal, B.S., et al., Oncogenic ERBB3 mutations in human cancers. Cancer Cell, 2013. 23(5): p. 603-17. DOI: https://doi.org/10.1016/j.ccr.2013.04.012

Mishra, R., et al., Oncogenic potential of ERBB3 mutations in human mammary epithelial cells. Cancer Res, 2017.77(4):(Suppl; pp. P4-21-22). DOI: https://doi.org/10.1158/1538-7445.SABCS16-P4-21-22

Newby, J.C., et al., Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res, 1997. 3(9): p. 1643-51.

Shou, J., et al., Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst, 2004. 96(12): p. 926-35. DOI: https://doi.org/10.1093/jnci/djh166

Tovey, S., et al., Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clin Cancer Res, 2005. 11(13): p. 4835-42.

Liu, B., et al., Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer, 2007. 120(9): p. 1874-82. DOI: https://doi.org/10.1002/ijc.22423

Clark, A.S., et al., Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther, 2002. 1(9): p. 707-17.

Jordan, N.J., et al., Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells. Breast Cancer Res Treat, 2004. 87(2): p. 167-80. DOI: https://doi.org/10.1023/B:BREA.0000041623.21338.47

Jathal, M.K., et al., Targeting ErbB3: the new RTK(id) on the prostate cancer block. Immunol Endocr Metab Agents Med Chem, 2011. 11(2): p. 131-149. DOI: https://doi.org/10.2174/187152211795495643

Hutcheson, I.R., et al., Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin beta1. Breast Cancer Res, 2011. 13(2): p. R29. DOI: https://doi.org/10.1186/bcr2848

Frogne, T., et al., Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat, 2009. 114(2): p. 263-75. DOI: https://doi.org/10.1007/s10549-008-0011-8

Vlacich, G. and R.J. Coffey, Resistance to EGFR-targeted therapy: a family affair. Cancer Cell, 2011. 20(4): p. 423-5. DOI: https://doi.org/10.1016/j.ccr.2011.10.006

Kruser, T.J. and D.L. Wheeler, Mechanisms of resistance to HER family targeting antibodies. Exp Cell Res, 2010. 316(7): p. 1083-100. DOI: https://doi.org/10.1016/j.yexcr.2010.01.009

Yonesaka, K., et al., Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med, 2011. 3(99): p. 99ra86. DOI: https://doi.org/10.1158/1538-7445.AM2012-4833

Huang, S., et al., Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res, 2013. 73(2): p. 824-33. DOI: https://doi.org/10.1158/0008-5472.CAN-12-1611

Engelman, J.A., et al., MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 2007. 316(5827): p. 1039-43. DOI: https://doi.org/10.1126/science.1141478

Abel, E.V., et al., Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest, 2013. 123(5): p. 2155-68. DOI: https://doi.org/10.1172/JCI65780

Montero-Conde, C., et al., Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov, 2013. 3(5): p. 520-33. DOI: https://doi.org/10.1158/2159-8290.CD-12-0531

Zhang, S., et al., Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med, 2011. 17(4): p. 461-9. DOI: https://doi.org/10.1038/nm.2309

Agus, D.B., et al., Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell, 2002. 2(2): p. 127-37. DOI: https://doi.org/10.1016/S1535-6108(02)00097-1

Lu, Y., et al., Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst, 2001. 93(24): p. 1852-7. DOI: https://doi.org/10.1093/jnci/93.24.1852

Nahta, R., et al., Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res, 2005. 65(23): p. 11118-28. DOI: https://doi.org/10.1158/0008-5472.CAN-04-3841

Huang, X., 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(3): p. 1204-14. DOI: https://doi.org/10.1158/0008-5472.CAN-09-3321

Chakrabarty, A., et al., Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A, 2012. 109(8): p. 2718-23. DOI: https://doi.org/10.1073/pnas.1018001108

Bezler, M., J.G. Hengstler, and A. Ullrich, Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells. Mol Oncol, 2012. 6(5): p. 516-29. DOI: https://doi.org/10.1016/j.molonc.2012.07.001

Knuefermann, C., et al., HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene, 2003. 22(21): p. 3205-12. DOI: https://doi.org/10.1038/sj.onc.1206394

Wang, S., et al., Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene, 2010. 29(29): p. 4225-36. DOI: https://doi.org/10.1038/onc.2010.180

Schoeberl, B., et al., An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res, 2010. 70(6): p. 2485-94. DOI: https://doi.org/10.1158/0008-5472.CAN-09-3145

Fitzgerald, J.B., et al., MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther, 2014. 13(2): p. 410-25. DOI: https://doi.org/10.1158/1535-7163.MCT-13-0255

McDonagh, C.F., et al., Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther, 2012. 11(3): p. 582-93. DOI: https://doi.org/10.1158/1535-7163.MCT-11-0820

Miller, M.J., et al., HER-3 peptide vaccines/mimics: Combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells. Oncoimmunology, 2014. 3(11): p. e956012. DOI: https://doi.org/10.4161/21624011.2014.956012

Sarup, J., et al., Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. Mol Cancer Ther, 2008. 7(10): p. 3223-36. DOI: https://doi.org/10.1158/1535-7163.MCT-07-2151

Huang, Z., et al., A pan-HER approach for cancer therapy: background, current status and future development. Expert Opin Biol Ther, 2009. 9(1): p. 97-110. DOI: https://doi.org/10.1517/14712590802630427

Wu, Y., et al., Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models. Mol Cancer Ther, 2013. 12(4): p. 427-37. DOI: https://doi.org/10.1158/1535-7163.MCT-12-0838

Xie, T., et al., Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol, 2014. 10(12): p. 1006-12. DOI: https://doi.org/10.1038/nchembio.1658

Kawakami, H., et al., The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget, 2014. 5(23): p. 11847-56. DOI: https://doi.org/10.18632/oncotarget.2663

Wakui, H., et al., Phase 1 and dose-finding study of patritumab (U3-1287), a human monoclonal antibody targeting HER3, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 2014. 73(3): p. 511-6. DOI: https://doi.org/10.1007/s00280-014-2375-2

Nishio, M., et al., Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer. Lung Cancer, 2015. 88(3): p. 275-81. DOI: https://doi.org/10.1016/j.lungcan.2015.03.010

Yonesaka, K., et al., Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. Oncogene, 2016. 35(7): p. 878-86. DOI: https://doi.org/10.1038/onc.2015.142

Daiichi Sankyo.Study of patritumab in combination with erlotinib in subjects with locally advanced or metastatic non-small-cell lung cancer (NSCLC). ClinicalTrials.gov 2018: NCT02134015.

Daiichi Sankyo. Patritumab with cetuximab and a platinum containing therapy for patients with head and neck cancer. ClinicalTrials.gov 2017: NCT02350712.

Daiichi Sankyo. Phase 1b/2 study of U3-1287 in combination with trastuzumab plus paclitaxel in newly diagnosed metastatic breast cancer (MBC). ClinicalTrials.gov 2017: NCT01512199.

Daiichi Sankyo. U3-1402 in metastatic or unresectable EGFR-mutant non-small cell lung cancer.ClinicalTrials.gov 2018: NCT03260491.

Merrimack. A study of MM-121 in combination with paclitaxel in patients with advanced gynecologic and breast cancers. ClinicalTrials.gov 2016: NCT01209195.

Merrimack. A safety study of MM-121 with cetuximab and irinotecan in patients with advanced cancers. ClinicalTrials.gov 2016:NCT01451632.

Frankie, A.H., et al, A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer.Cancer Res, 2014. 77(9):(Suppl;pp. P3-11-03).

Merrimack. Phase I safety study of the drug MM-121 in patients with advanced solid tumors resisting ordinary treatment. ClinicalTrials.gov 2016:NCT00734305.

Liu, J.F., et al., Randomized phase II trial of seribantumab in combination with paclitaxel in patients with advanced platinum-resistant or -refractory ovarian cancer. J Clin Oncol, 2016. 34(36): p. 4345-4353. DOI: https://doi.org/10.1200/JCO.2016.67.1891

Wang, S., et al., Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer. Breast Cancer Res, 2013. 15(5): p. R101. DOI: https://doi.org/10.1186/bcr3563

Huang, J., et al., The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer, 2013. 12(1): p. 134. DOI: https://doi.org/10.1186/1476-4598-12-134

Jiang, N., et al., Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma. Mol Cancer Ther, 2014. 13(7): p. 1826-36. DOI: https://doi.org/10.1158/1535-7163.MCT-13-1093

Merrimack. A study of MM-121 in combination with chemotherapy versus chemotherapy alone in heregulin positive NSCLC. ClinicalTrials.gov 2018: NCT02387216.

Lecia, V.S., et al, A phase 2 study of seribantumab (MM-121) in combination with docetaxel or pemetrexed versus docetaxel or pemetrexed alone in patients with heregulin positive (HRG+), locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol, 2016. 34(15) :(suppl; abstr TPS9110).

Merrimack. A study of MM-121 combination therapy in patients with advanced non-small cell lung cancer. ClinicalTrials.gov 2016: NCT00994123.

Merrimack. Phase 2 trial of seribantumab plus fulvestrant in postmenopausal women with metastatic breast cancer (SHERBOC).ClinicalTrials.gov 2017: NCT03241810.

Moyo, V.M., A randomized, double-blind phase II trial of exemestane with or without MM-121 in postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+), HER2-negative breast cancer. J Clin Oncol, 2015. 29(15): (Suppl. abstr TPS112). DOI: https://doi.org/10.1200/jco.2011.29.15_suppl.tps112

Merrimack. Phase 1 combination study of MM-151 with MM-121, MM-141, or trametinib. ClinicalTrials.gov 2016: NCT02538627.

Arnedos, M., A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors. J Clin Oncol, 2013. 31(15): (suppl; abstr 2609 ). DOI: https://doi.org/10.1200/jco.2013.31.15_suppl.2609

Sanofi. A study of investigational SAR256212 in combination with SAR245408 in patients with solid tumor cancers.ClinicalTrials.gov 2014: NCT01436565.

Meneses-Lorente, G., et al., Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-HER3 antibody. Cancer Chemother Pharmacol, 2015. 75(4): p. 837-50. DOI: https://doi.org/10.1007/s00280-015-2697-8

Mirschberger, C., et al., RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res, 2013. 73(16): p. 5183-94. DOI: https://doi.org/10.1158/0008-5472.CAN-13-0099

Roche. A study to evaluate RO5479599 in combination with perjeta (pertuzumab) and paclitaxel in patients with metastatic breast cancer expressing HER3 & HER2 protein. ClinicalTrials.gov 2017: NCT01918254.

Meulendijks, D., 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(4): p. 877-85. DOI: https://doi.org/10.1158/1078-0432.CCR-15-1683

Roche. A study evaluating RO5479599 in combination with carboplatin and paclitaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) of squamous histology. ClinicalTrials.gov 2017: NCT02204345.

Meulendijks, D., et al., Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity. Clin Cancer Res, 2017. 23(18): p. 5406-5415. DOI: https://doi.org/10.1158/1078-0432.CCR-17-0812

Garner, A.P., et al., An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res, 2013. 73(19): p. 6024-35. DOI: https://doi.org/10.1158/0008-5472.CAN-13-1198

Garrett, J.T., et al., Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. Cancer Res, 2013. 73(19): p. 6013-23. DOI: https://doi.org/10.1158/0008-5472.CAN-13-1191

Novartis. Study of efficacy and safety of LJM716 and cetuximab in head and neck squamous cell carcinoma patients. ClinicalTrials.gov 2016: NCT02143622.

Novartis. Open-label study evaluating the safety and tolerability of LJM716, BYL719 and trastuzumab in patients with metastatic HER2+ breast cancer. ClinicalTrials.gov 2017: NCT02167854.

Novartis. Phase I study LJM716 combined with trastuzumab in patients with HER2 overexpressing metastatic breast or gastric cancer. ClinicalTrials.gov 2017: NCT01602406.

Novartis. Study of safety & efficacy of the combination of LJM716 & BYL719 in patients with previously treated esophageal squamous cell carcinoma (ESCC). ClinicalTrials.gov 2017: NCT01822613.

Reynolds. K.L., et al., A phase 1 study of LJM716 in patients with esophageal squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic breast or gastric cancer. J Clin Oncol, 2014. 32(5): (suppl; abstr 2517). DOI: https://doi.org/10.1200/jco.2014.32.15_suppl.2517

Esaki. T., et al., Phase I study of the safety and tolerability of LJM716 in Japanese patients with advanced solid tumors. Mol Can Ther, 2015. 14(12):pp. C120. DOI: https://doi.org/10.1158/1535-7163.TARG-15-C120

Xiao, Z., et al., A potent HER3 monoclonal antibody that blocks both ligand-dependent and -independent activities: differential impacts of PTEN status on tumor response. Mol Cancer Ther, 2016. 15(4): p. 689-701. DOI: https://doi.org/10.1158/1535-7163.MCT-15-0555

Kolltan. A phase 1 study to evaluate the safety and pharmacokinetics of KTN3379 in adult subjects with advanced tumors. ClinicalTrials.gov 2017: NCT02014909.

Bauer, T.M., et al., A phase 1, open-label study to evaluate the safety and pharmacokinetics of the anti ErbB3 antibody, KTN3379, alone or in combination with targeted therapies in patients with advanced tumors. J Clin Oncol, 2015. 33 (15): (suppl; abstr 2598). DOI: https://doi.org/10.1200/jco.2015.33.15_suppl.2598

Celledex Therapeutics. Enhancing radioiodine incorporation into BRAF mutant thyroid cancers with the combination of vemurafenib and KTN3379. ClinicalTrials.gov 2017: NCT02456701.

Celldex Therapeutics. A window of opportunity study of KTN3379 in surgically resectable Head and Neck cancer patients. ClinicalTrials.gov 2017: NCT02473731.

Meetze, K., et al., Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. Clin Cancer Res, 2015. 21(5): p. 1106-14. DOI: https://doi.org/10.1158/1078-0432.CCR-14-2407

AVEO. A phase 1 dose escalation study of AV-203, an ERBB3 inhibitory antibody, in subjects with advanced solid tumors. ClinicalTrials.gov 2015: NCT01603979.

GlaxoSmithKline. Dose escalation study to investigate the safety, pharmacokinetics, and pharmacodynamics of GSK2849330 in subjects with advanced HER3-positive solid tumors. ClinicalTrials.gov 2017: NCT01966445.

GlaxoSmithKline. Immuno positron emission tomography study of GSK2849330 in subjects with human epidermal growth factor receptor 3-positive solid tumors. ClinicalTrials.gov 2017: NCT02345174.

Papadopoulos, K.P., et al., Phase I study of REGN1400 (anti-ErbB3) combined with erlotinib or cetuximab in patients (pts) with advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or head and neck cancer (SCCHN). J Clin Oncol, 2014.32(15): p.2516. DOI: https://doi.org/10.1200/jco.2014.32.15_suppl.2516

Zhang, L., et al., ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models. Mol Cancer Ther, 2014. 13(5): p. 1345-55. DOI: https://doi.org/10.1158/1535-7163.MCT-13-1033

Sala, G., et al., An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene, 2012. 31(10): p. 1275-86. DOI: https://doi.org/10.1038/onc.2011.322

Schaefer, G., et al., A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell, 2011. 20(4): p. 472-86. DOI: https://doi.org/10.1016/j.ccr.2011.09.003

Kamath, A.V., et al., Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose. Cancer Chemother Pharmacol, 2012. 69(4): p. 1063-9. DOI: https://doi.org/10.1007/s00280-011-1806-6

Juric, D., et al., Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors. Clin Cancer Res, 2015. 21(11): p. 2462-70. DOI: https://doi.org/10.1158/1078-0432.CCR-14-2412

Genentech. A study of MEHD7945A and cobimetinib (GDC-0973) in patients with locally advanced or metastatic cancers with mutant KRAS. ClinicalTrials.gov 2016: NCT01986166.

Genentech. A study of MEHD7945A + FOLFIRI versus cetuximab + FOLFIRI in second line in patients with KRAS wild-type metastatic colorectal cancer. ClinicalTrials.gov 2016: NCT01652482.

Genentech. A study of MEHD7945A versus cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. ClinicalTrials.gov 2016: NCT01577173.

Jimeno, A., et al., Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer, 2016. 122(24): p. 3803-3811. DOI: https://doi.org/10.1002/cncr.30256

Denlinger. C.S., et al., Randomized open-label phase 2 study of MM-111 and paclitaxel (PTX) with trastuzumab (TRAS) in patients with HER2-expressing carcinomas of the distal esophagus, gastroesophageal (GE) junction, and stomach who have failed front-line metastatic or locally advanced therapy. J Clin Oncol, 2014. 32 (5): (suppl; abstr TPS4148). DOI: https://doi.org/10.1200/jco.2014.32.15_suppl.tps4148

Merrimack. A study of MM-111 in patients with advanced, refractory HER2 amplified, heregulin positive cancers (monotherapy).ClinicalTrials.gov 2015: NCT00911898.

Merrimack. MM-111 in combination with herceptin in patients with advanced HER2 amplified, heregulin positive breast cancer. ClinicalTrials.gov 2015: NCT01097460.

Richards. D.A., et al., A phase 1 study of MM-111, a bispecific HER2/HER3 antibody fusion protein, combined with multiple treatment regimens in patients with advanced HER2-positive solid tumors. J Clin Oncol, 2014. 32 (15): (suppl; abstr 651).

Merrimack. A phase 1 study of MM-141 in patients with advanced solid tumors. ClinicalTrials.gov 2016: NCT01733004.

Ko, A.H., et al., A multicenter phase II study of istiratumab (MM-141) plus nab-paclitaxel (A) and gemcitabine (G) in metastatic pancreatic cancer (MPC). J Clin Oncol, 2016. 34(5): (suppl; abstr TPS481). DOI: https://doi.org/10.1200/jco.2016.34.4_suppl.tps481

Calvo. E., et al. A phase I/II study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3, in patients with solid tumors. Cancer Res, 2016. 76 (14):(Suppl; pp. CT050). DOI: https://doi.org/10.1158/1538-7445.AM2016-CT050

Merus N.V. MCLA-128 With trastuzumab/chemotherapy in HER2+ and with endocrine Therapy in ER+ and Low HER2 breast cancer.ClinicalTrials.gov 2016: NCT03321981.

Farooqi, A.A., Z.U. Rehman, and J. Muntane, Antisense therapeutics in oncology: current status. Onco Targets Ther, 2014. 7: p. 2035-42. DOI: https://doi.org/10.2147/OTT.S49652

Jacobsen, H.J., et al., Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity. Clin Cancer Res, 2015. 21(18): p. 4110-22. DOI: https://doi.org/10.1158/1078-0432.CCR-14-3312

Francis, D.M., et al., Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models. Clin Cancer Res, 2016. 22(3): p. 633-43. DOI: https://doi.org/10.1158/1078-0432.CCR-15-1664

Symphogen. Sym013 (Pan-HER) in patients with advanced epithelial malignancies. ClinicalTrials.gov 2017: NCT02906670.

Mendell, J., et al., Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer. EBioMedicine, 2015. 2(3): p. 264-71. DOI: https://doi.org/10.1016/j.ebiom.2015.02.005

Karachaliou, N. and R. Rosell, Evaluation of Biomarkers for HER3-targeted Therapies in Cancer. EBioMedicine, 2015. 2(3): p. 192-3. DOI: https://doi.org/10.1016/j.ebiom.2015.02.010

Sarantoloulos, J.M.S.G., et al., First-in-human phase 1 dose-escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or advanced solid tumors. J Clin Oncol, 2014. 32(5): (suppl; abstr 11113). DOI: https://doi.org/10.1200/jco.2014.32.15_suppl.11113

Shames, D.S., et al., High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck. PLoS One, 2013. 8(2): p. e56765. DOI: https://doi.org/10.1371/journal.pone.0056765

Holbro, T., et al., The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A, 2003. 100(15): p. 8933-8. DOI: https://doi.org/10.1073/pnas.1537685100

HER3, monoclonal antibodies, targeted therapy.
  • Abstract views: 5908

  • PDF: 1960
  • HTML: 532
How to Cite
Mishra, R., Patel, H., Alanazi, S., Yuan, L., & Garrett, J. T. (2018). HER3 signaling and targeted therapy in cancer. Oncology Reviews, 12(1). https://doi.org/10.4081/oncol.2018.355