HER3/ErbB3, an emerging cancer therapeutic target

Acta Biochimica et Biophysica Sinica

Volumn 48, Issue 1, 2015, Pages 39-48

  Zhang, Ningyan ^a   Chang, Yujun ^b   Rios, Adan ^a   An, Zhiqiang ^a  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b PanaMab Inc   (United States)

Author keywords

biomarkers; cancer therapy; HER3 ErbB3; monoclonal antibody (mAb)

Indexed keywords

ANTINEOPLASTIC AGENT; ANTISENSE OLIGONUCLEOTIDE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 3; ERBB3 PROTEIN, HUMAN; ESCRT PROTEIN; MONOCLONAL ANTIBODY; NEDD4 UBIQUITIN PROTEIN LIGASES; NEU DIFFERENTIATION FACTOR; RNF41 PROTEIN, HUMAN; TUMOR MARKER; UBIQUITIN PROTEIN LIGASE;

ANIMAL; CHEMISTRY; GENETICS; HUMAN; METABOLISM; MUTATION; NEOPLASMS; PROTEIN MULTIMERIZATION; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; ENDOSOMAL SORTING COMPLEXES REQUIRED FOR TRANSPORT; HUMANS; MUTATION; NEOPLASMS; NEUREGULIN-1; OLIGONUCLEOTIDES, ANTISENSE; PROTEIN MULTIMERIZATION; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, ERBB-3; SIGNAL TRANSDUCTION; UBIQUITIN-PROTEIN LIGASES;

EID: 84960444297     PISSN: 16729145     EISSN: 17457270     Source Type: Journal    
DOI: 10.1093/abbs/gmv103     Document Type: Review

References (122)

1. Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer 2013, 13: 663-673.
2. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. CancerRes 2008, 68: 5878-5887.
3. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007, 445: 437-441.
4. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007, 316: 1039-1043.
5. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004, 305: 1163-1167.
6. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004, 304: 1497-1500.
7. Casalini P, Iorio MV, Galmozzi E, Menard S. Role of HER receptors family in development and differentiation. J Cell Physiol 2004, 200: 343-350.
8. Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995, 378: 394-398.
9. Albanell J, Baselga J. Trastuzumab, a humanized anti-HER2 monoclonal antibody, for the treatment of breast cancer. Drugs Today (Barc) 1999, 35: 931-946.
10. Amann J, Kalyankrishna S, Massion PP, Ohm JE, Girard L, Shigematsu H, Peyton M, et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 2005, 65: 226-235.
11. Rusnak DW, Alligood KJ, Mullin RJ, Spehar GM, Arenas-Elliott C, Martin AM, Degenhardt Y, et al. Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines. Cell Prolif 2007, 40: 580-594.
12. Valentini AM, Pirrelli M, Caruso ML. EGFR-targeted therapy in colorectal cancer: does immunohistochemistry deserve a role in predicting the response to cetuximab? Curr Opin Mol Ther 2008, 10: 124-131.
13. Friess T, Scheuer W, Hasmann M. Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. Clin Cancer Res 2005, 11: 5300-5309.
14. Easley C, Kirkpatrick P. Panitumumab. Nat Rev Drug Discov 2006, 5: 987-988.
15. Chung A, Cui X, Audeh W, Giuliano A. Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. Clin Breast Cancer 2013, 13: 223-232.
16. Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med 2007, 357: 39-51.
17. Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Cetuximab and panitumumab in KRAS wild-type colorectal cancer: a meta-analysis. Int J Colorectal Dis 2011, 26: 823-833.
18. Paliga A, Onerheim R, Gologan A, Chong G, Spatz A, Niazi T, Garant A, et al. EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors? Br J Cancer 2012, 107: 1864-1868.
19. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 2008, 27: 3944-3956.
20. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 2007, 97: 1139-1145.
21. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in resistant breast carcinoma cells. Cancer Res 2009, 69: 2191-2194.
22. Shattuck DL, Miller JK, Carraway KL III, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 2008, 68: 1471-1477.
23. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004, 6: 117-127.
24. Kong A, Calleja V, Leboucher P, Harris A, Parker PJ, Larijani B. HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells. PLoS One 2008, 3: e2881.
25. Sierke SL, Cheng K, Kim HH, Koland JG. Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochem J 1997, 322 (Pt 3): 757-763.
26. Berger MB, Mendrola JM, Lemmon MA. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett 2004, 569: 332-336.
27. Suenaga A, Takada N, Hatakeyama M, Ichikawa M, Yu X, Tomii K, Okimoto N, et al. Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides. J Biol Chem 2005, 280: 1321-1326.
28. Mattoon DR, Lamothe B, Lax I, Schlessinger J. The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway. BMC Biol 2004, 2: 24.
29. Reschke M, Mihic-Probst D, van der Horst EH, Knyazev P, Wild PJ, Hutterer M, Meyer S, et al. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res 2008, 14: 5188-5197.
30. Frolov A, Schuller K, Tzeng CW, Cannon EE, Ku BC, Howard JH, Vickers SM, et al. ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib. Cancer Biol Ther 2007, 6: 548-554.
31. van der Horst EH, Murgia M, Treder M, Ullrich A. Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies. Int J Cancer 2005, 115: 519-527.
32. Jiang X, Borgesi RA, McKnight NC, Kaur R, Carpenter CL, Balk SP. Activation of nonreceptor tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and ErbB3 in prostate cancer cells. J Biol Chem 2007, 282: 32689-32698.
33. Nagumo Y, Faratian D, Mullen P, Harrison DJ, Hasmann M, Langdon SP. Modulation of HER3 is a marker of dynamic cell signaling in ovarian cancer: implications for pertuzumab sensitivity. Mol Cancer Res 2009, 7: 1563-1571.
34. Yoon YK, Kim HP, Han SW, Hur HS, Oh do Y, Im SA, Bang YJ, et al. Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. Mol Cancer Ther 2009, 8: 2526-2536.
35. Choi B-K, Fan X, Deng H, Zhang N, An Z. HER3 (ERBB3) is a key sensor in the regulation of ERBB-mediated signaling in both low and high HER2 (ERBB2) expressing cancer cells. Cancer Med 2012, 1: 28-38.
36. Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 2013, 23: 603-617.
37. Jeong EG, Soung YH, Lee JW, Lee SH, Nam SW, Lee JY, Yoo NJ, et al. ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas. Int J Cancer 2006, 119: 2986-2987.
38. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 2009, 9: 463-475.
39. Aurisicchio L, Marra E, Roscilli G, Mancini R, Ciliberto G. The promise of anti-ErbB3 monoclonals as new cancer therapeutics. Oncotarget 2012, 3: 744-758.
40. Campbell MR, Amin D, Moasser MM. HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res 2010, 16: 1373-1383.
41. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001, 2: 127-137.
42. Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012, 12: 553-563.
43. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003, 21: 2787-2799.
44. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res 2003, 284: 99-110.
45. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000, 19: 3159-3167.
46. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003, 12: 541-552.
47. Carraway KL III. E3 ubiquitin ligases in ErbB receptor quantity control. Semin Cell Dev Biol 2010, 21: 936-943.
48. Sithanandam G, Anderson LM. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 2008, 15: 413-448.
49. Amin DN, Sergina N, Ahuja D, McMahon M, Blair JA, Wang D, Hann B, et al. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver. Sci Transl Med 2010, 2: 16ra17.
50. Gala K, Chandarlapaty S. Molecular pathways: HER3 targeted therapy. Clin Cancer Res 2014, 20: 1410-1416.
51. Kol A, Terwisscha van Scheltinga AG, Timmer-Bosscha H, Lamberts LE, Bensch F, de Vries EG, Schroder CP. HER3, serious partner in crime: therapeutic approaches and potential biomarkers for effect of HER3- targeting. Pharmacol Therapeut 2014, 143: 1-11.
52. Mujoo K, Choi BK, Huang Z, Zhang N, An Z. Regulation of ERBB3/ HER3 signaling in cancer. Oncotarget 2014, 5: 10222-10236.
53. Macbeath G, Adiwijaya B, Liu J, Sequist LV, Pujade-Lauraine E, Higgins M, Tabah-Fisch I, et al. A meta-analysis of biomarkers in three randomized, Phase 2 studies of MM-121, a ligand-blocking anti-erbB3 antibody, in patients with ovarian, lung, and breast cancers. Annal Oncol 2014, 25 (suppl-4): iv58-iv84.
54. Naidu R, Yadav M, Nair S, Kutty MK. Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer 1998, 78: 1385-1390.
55. Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E, Prigent SA, et al. Expression of the ERBB3 gene product in breast cancer. Br J Cancer 1992, 66: 1116-1121.
56. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003, 200: 290-297.
57. Choi BK, Cai X, Yuan B, Huang Z, Fan X, Deng H, Zhang N, et al. HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways. Protein Cell 2012, 3: 781-789.
58. Chen L, Siddiqui S, Bose S, Mooso B, Asuncion A, Bedolla RG, Vinall R, et al. Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. Cancer Res 2010, 70: 5994-6003.
59. Qiu XB, Goldberg AL. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci USA 2002, 99: 14843-14848.
60. Huang Z, Choi BK, Mujoo K, Fan X, Fa M, Mukherjee S, Owiti N, et al. The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling. Oncogene 2014, 56: 1-11.
61. Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 2010, 70: 2485-2494.
62. Fitzgerald JB, Johnson BW, Baum J, Adams S, Iadevaia S, Tang J, Rimkunas V, 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: 410-425.
63. McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, Zhang B, 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: 582-593.
64. Kirouac DC, Du JY, Lahdenranta J, Overland R, Yarar D, Paragas V, Pace E, et al. Computational modeling of ERBB2-amplified breast cancer identifies combined ErbB2/3 blockade as superior to the combination of MEK and AKT inhibitors. Sci Signal 2013, 6: ra68.
65. Schaefer G, Haber L, Crocker LM, Shia S, Shao L, Dowbenko D, Totpal K, et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 2011, 20: 472-486.
66. Kamath AV, Lu D, Gupta P, Jin D, Xiang H, Wong A, Leddy C, 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: 1063-1069.
67. Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, et al. Dual targeting of EGFR and HER3 withMEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res 2013, 73: 824-833.
68. Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, Weitsman G, et al. Antagonismof EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal 2014, 7: ra29.
69. Miller MJ, Foy KC, Overholser JP, Nahta R, Kaumaya PT. 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. Oncoimmunol 2014, 3: e956012.
70. Huang Z, Brdlik C, Jin P, Shepard HM. A pan-HER approach for cancer therapy: background, current status and future development. Expert Opin Biol Ther 2009, 9: 97-110.
71. Sarup J, Jin P, Turin L, Bai X, Beryt M, Brdlik C, Higaki JN, 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: 3223-3236.
72. Wu Y, Zhang Y, Wang M, Li Q, Qu Z, Shi V, Kraft P, 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: 427-437.
73. Xie T, Lim SM, Westover KD, Dodge ME, Ercan D, Ficarro SB, Udayakumar D, et al. Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol 2014, 10: 1006-1012.
74. Wakui H, Yamamoto N, Nakamichi S, Tamura Y, Nokihara H, Yamada Y, Tamura T. 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: 511-516.
75. Nishio M, Horiike A, Murakami H, Yamamoto N, Kaneda H, Nakagawa K, Horinouchi H, 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: 275-281.
76. Yonesaka K, Hirotani K, Kawakami H, Takeda M, Kaneda H, Sakai K, Okamoto I, et al. Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. Oncogene 2015, doi: 10.1038/onc.2015.142.
77. Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, Sakamoto H, et al. The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget 2014, 5: 11847-11856.
78. Sankyo D. Study of patritumab in combination with erlotinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC). ClinicalTrialsgov 2015: NCT02134015.
79. Sankyo D. A study using patritumab in combination with cetuximab and a platinum containing therapy for patients with head and neck cancer. ClinicalTrialsgov 2015: NCT02350712.
80. LoRusso P, Janne PA, Oliveira M, Rizvi N, Malburg L, Keedy V, Yee L, 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: 3078-3087.
81. Wang S, Huang J, Lyu H, Cai B, Yang X, Li F, Tan J, 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: R101.
82. Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, Liu B. 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: 134.
83. Jiang N, Wang D, Hu Z, Shin HJ, Qian G, Rahman MA, Zhang H, 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: 1826-1836.
84. Merrimack. A study of MM-121 in combination with chemotherapy versus chemotherapy alone in heregulin positive NSCLC. ClinicalTrialsgov 2015: NCT02387216.
85. Schoeberl B, Pace EA, Fitzgerald JB, Harms BD, Xu L, Nie L, Linggi B, et al. Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal 2009, 2: ra31.
86. Merrimack. A study of investigational SAR256212 in combination with SAR245408 in patients with solid tumor cancers. ClinicalTrialsgov 2014: NCT01436565.
87. Merrimack. Phase I safety study of the drug MM-121 in patients with advanced solid tumors resisting ordinary Treatment. ClinicalTrialsgov 2014: NCT00734305.
88. 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. ClinicalTrialsgov 2015: NCT02204345.
89. Roche. A study to evaluate RO5479599 in combination with perjeta (Pertuzumab) and paclitaxel in patients with metastatic breast cancer expressing HER3 & HER2 protein. ClinicalTrialsgov 2015: NCT01918254.
90. Roche. A study of RO5479599 alone or in combination with cetuximab or erlotinib in patients with metastatic and/or locally advanced malignant HER3-positive solid tumors. ClinicalTrialsgov 2015: NCT01482377.
91. Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 2013, 73: 6024-6035.
92. Garrett JT, Sutton CR, Kurupi R, Bialucha CU, Ettenberg SA, Collins SD, Sheng Q, 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: 6013-6023.
93. Novartis. Study of efficacy and safety of LJM716 and cetuximab in head and neck squamous cell carcinoma patients. ClinicalTrialsgov 2014: NCT02143622.
94. Novartis. Open-label study evaluating the safety and tolerability of LJM716, BYL719 and trastuzumab in patients with metastatic HER2+ breast cancer. ClinicalTrialsgov 2015: NCT02167854.
95. Novartis. Phase I study LJM716 combined with trastuzumab in patients with HER2 overexpressing metastatic breast or gastric cancer. Clinical-Trialsgov 2015: NCT01602406.
96. Novartis. Study of safety & efficacy of the combination of LJM716 & BYL719 in patients with previously treated esophageal squamous cell carcinoma (ESCC). ClinicalTrialsgov 2015: NCT01822613.
97. GlaxoSmithKline. Dose escalation study to investigate the safety, pharmacokinetics, and pharmacodynamics of GSK2849330 in subjects with advanced Her3-positive solid tumors. ClinicalTrialsgov 2015: NCT01966445.
98. GlaxoSmithKline. Immuno positron emission tomography study of GSK2849330 in subjects with human epidermal growth factor receptor 3-positive solid tumors. ClinicalTrialsgov 2015: NCT02345174.
99. Kolltan. A phase 1 study to evaluate the safety and pharmacokinetics of KTN3379 in adult subjects with advanced tumors. ClinicalTrialsgov 2015: NCT02014909.
100. Meetze K, Vincent S, Tyler S, Mazsa EK, Delpero AR, Bottega S, McIntosh D, 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: 1106-1114.
101. AVEO. A phase 1 dose escalation study of AV-203, an ERBB3 inhibitory antibody, in subjects with advanced solid tumors. ClinicalTrialsgov 2015: NCT01603979.
102. Zhang L, Castanaro C, Luan B, Yang K, Fan L, Fairhurst JL, Rafique A, et al. ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models. Mol Cancer Ther 2014, 13: 1345-1355.
103. Regeneron. Study of REGN1400 alone and in combination with erlotinib or cetuximab in patients with certain types of cancer. ClinicalTrialsgov 2015: NCT01727869.
104. Xu L, Kohli N, Rennard R, Jiao Y, Razlog M, Zhang K, Baum J, et al. Rapid optimization and prototyping for therapeutic antibody-like molecules. MAbs 2013, 5: 237-254.
105. Genentech. A study of MEHD7945A and cobimetinib (GDC-0973) in patients with locally advanced or metastatic cancers with mutant KRAS. ClinicalTrialsgov 2015: NCT01986166.
106. Genentech. A study of MEHD7945A + FOLFIRI versus cetuximab + FOLFIRI in second line in patients with KRAS wild-type metastatic colorectal cancer. ClinicalTrialsgov 2015: NCT01652482.
107. Sankyo D. Phase 1b/2 study of U3-1287 in combination with trastuzumab plus paclitaxel in newly diagnosed metastatic breast cancer (MBC). ClinicalTrialsgov 2015: NCT01512199.
108. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009, 14: 320-368.
109. Meneses-Lorente G, Friess T, Kolm I, Holzlwimmer G, Bader S, Meille C, Thomas M, et al. Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-HER3 antibody. Cancer Chemother Pharmacol 2015, 75: 837-850.
110. Bauer TM, Infante JR, Eder JP, LoRusso P, LaVallee T, Gedrich R, Sidor C, 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: (suppl: abstr 2598).
111. Lynce F, Swain SM. Pertuzumab for the treatment of breast cancer. Cancer Invest 2014, 32: 430-438.
112. Merrimack. MM-111 in combination with herceptin inpatients with advanced Her2 amplified, heregulin positive breast cancer. ClinicalTrialsgov 2014: NCT01097460.
113. Merrimack. A study of MM-111 in patients with advanced, refractory Her2 amplified, heregulin positive cancers (monotherapy). ClinicalTrialsgov 2014: NCT00911898.
114. Merrimack. A study of MM-111 and paclitaxel with trastuzumab in patients HER2 positive carcinomas of the distal esophagus, gastroesophageal (GE) junction and stomach. ClinicalTrialsgov 2015: NCT01774851.
115. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, Fartoux L, Venot C, Bladt F, Housset C, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 2009, 15: 5445-5456.
116. Isakoff SJ, Arnedos M, Soria J-C, Bahleda R, Shields A, LoRusso PM, Saleh M. Pre-clinical characterization and first in human study of MM-141, an antibody inhibitor of IGF-1R and ErbB3. AACR 2015: Abstract #CT237.
117. Merrimack. A phase 1 study of MM-141 in patients with advanced solid tumors. ClinicalTrialsgov 2014: NCT01733004.
118. Merrimack. A phase 2 study of MM-141 plus Nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). ClinicalTrialsgov 2015: NCT02399137.
119. Francis D, Huang S, Werner L, Lantto J, Horak ID, Kragh M, Harari PM. Sym013, novel pan-HER monoclonal antibody mixture, augments radiation response in human lung and head and neck tumors. Cancer Res 2014, 74: 4495.
120. Kaumaya PT. Bridging oncology and immunology: expanding horizons with innovative peptide vaccines and peptidomimetics. Immunotherapy 2013, 5: 1159-1163.
121. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 2001, 61: 4744-4749.
122. Farooqi AA, Rehman ZU, Muntane J. Antisense therapeutics in oncology: current status. OncoTargets Ther 2014, 7: 2035-2042.