Abstract
Trastuzumab is a monoclonal antibody targeted against the human epidermal growth factor receptor (HER) 2 tyrosine kinase receptor, which is overexpressed in approximately 25% of invasive breast cancers. The majority of patients with metastatic breast cancer who initially respond to trastuzumab, however, demonstrate disease progression within 1 year of treatment initiation. Preclinical studies have indicated several molecular mechanisms that could contribute to the development of trastuzumab resistance. Increased signaling via the phosphatidylinositol 3-kinase/Akt pathway could contribute to trastuzumab resistance because of activation of multiple receptor pathways that include HER2-related receptors or non-HER receptors such as the insulin-like growth factor 1 receptor, which appears to be involved in a cross-talk with HER2 in resistant cells. Additionally, loss of function of the tumor suppressor PTEN gene, the negative regulator of Akt, results in heightened Akt signaling that leads to decreased sensitivity to trastuzumab. Decreased interaction between trastuzumab and its target receptor HER2, which is due to steric hindrance of HER2 by cell surface proteins such as mucin-4 (MUC4), may block the inhibitory actions of trastuzumab. Novel therapies targeted against these aberrant molecular pathways offer hope that the effectiveness and duration of response to trastuzumab can be greatly improved.
Key Points
-
Based on the results of the phase III trials, trastuzumab can increase median survival when combined with standard chemotherapy in patients with breast cancer
-
Mechanisms of action of trastuzumab include inhibition of HER2 extracellular domain proteolysis, disruption of downstream signaling pathways, G1 cell-cycle arrest, inhibition of DNA repair, suppression of angiogenesis, and induction of antibody-dependent cellular cytotoxicity
-
Potential mechanisms of trastuzumab resistance include altered receptor-antibody interaction, increased cell signaling from other HER receptors, increased Akt activity, reduced PTEN level, reduced p27kip1, and increased IGF-IR signaling
-
There is an urgent need to identify biomarkers to guide anti-HER-2 therapy in patients who develop progressive metastatic breast cancer while receiving trastuzumab, and to identify combination therapies using novel anti-HER-2 agents
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Carter P et al. (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289
Slamon DJ et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182
Slamon DJ et al. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712
Esteva FJ et al. (2005) Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Cancer Res 7: 436–443
Joensuu H et al. (2003) Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study. Clin Cancer Res 9: 923–930
Leonard DS et al. (2002) Anti-human epidermal growth factor receptor 2 monoclonal antibody therapy for breast cancer. Br J Surg 89: 262–271
Press MF et al. (1997) HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 15: 2894–2904
Press MF et al. (2002) Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol 20: 3095–3105
Muss HB et al. (1994) c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330: 1260–1266
Paik S et al. (1998) erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90: 1361–1370
Thor AD et al. (1998) erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90: 1346–1360
Ross JS et al. (2004) Targeted therapy in breast cancer: the HER-2/neu gene and protein. Mol Cell Proteomics 3: 379–398
Eceles SA (2001) The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J Mamm Gland Biol Neoplasia 6: 393–406
Paik S et al. (1990) Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 8: 103–112
Niehans GA et al. (1993) Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst 85: 1230–1235
Nahta R and Esteva FJ (2003) HER-2-targeted therapy: lessons learned and future directions. Clin Cancer Res 9: 5078–5084
Nahta R and Esteva FJ (2006) Herceptin: mechanisms of action and resistance. Cancer Lett 232: 123–138
Baselga J et al. (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28 (Suppl 16): S4–S11
Sliwkowski M et al. (1999) Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 26 (Suppl 12): S60–S70
Arnould L et al. (2006) Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Brit J Cancer 94: 259–267
Gennari R et al. (2004) Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 10: 5650–5655
Carter P et al. (1992) Humanization of an anti-p185her2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289
Cooley S et al. (1999) Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. Exp Hematol 27: 1533–1541
Lewis GD et al. (1993) Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37: 255–263
Stockmeyer B et al. (2003) Polymorphonuclear granulocytes induce antibody-dependent apoptosis in human breast cancer cells. J Immunol 171: 5124–5129
Clynes RA et al. (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6: 443–446
Repka T et al. (2003) Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study. Clin Cancer Res 9: 2440–2446
Baselga J et al.(1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14: 737–744
Cobleigh MA et al. (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER-2 overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17: 2639–2648
Vogel CL et al. (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20: 719–726
Seidman AD et al. (2001) Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19: 2587–2595
Slamon DJ et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792
Esteva F J et al. (2002) Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20: 1800–1808
Price-Schiavi SA et al. (2002) Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int J Cancer 99: 783–791
Nagy P et al. (2005) Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res 65: 473–482
Carraway KL et al. (2001) Muc4/sialomucin complex in the mammary gland and breast cancer. J Mammary Gland Biol Neoplasia 6: 323–337
Akiyama T et al. (1991) The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. Mol Cell Biol 11: 833–842
Tanner M et al. (2004) Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. Mol Cancer Ther 3: 1585–1592
Paez JG et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500
Stephens P et al. (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431: 525–526
Hubbard SR et al. (1998) Autoregulatory mechanisms in protein-tyrosine kinases. J Biol Chem 273: 11987–11990
Lynch TJ et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139
Chang KL and Lau SK . (2005) EGFR mutations in non-small cell lung carcinomas may predict response to gefitinib: extension of an emerging paradigm. Adv Anat Pathol 12: 47–52
Lee JW et al. (2006) Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12: 57–61
Burstein HJ et al. (2003) Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21: 2889–2895
Graus-Porta D et al. (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16: 1647–1655
Diermeier S et al. (2005) Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. Exp Cell Res 304: 604–619
Motoyama AB et al. (2002) The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 62: 3151–3158
Wick M et al. (1995) Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. Exp Cell Res 219: 527–535
Anastasi S et al. (2005) Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene 24: 4540–4548
Fiorentino L et al. (2000) Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 20: 7735–7750
Hackel PO et al. (2001) Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biol Chem 382: 1649–1662
Lu YH et al. (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93: 1852–1857
Lu Y et al. (2004) Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 108: 334–341
Nahta R et al. (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65: 11118–11128
Yakes FM et al. (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62: 4132–4141
Chan CT et al. (2005) Differential sensitivities of trastuzumab (Herceptin)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors. Breast Cancer Res Treat 91: 187–201
Nagata Y et al. (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6: 117–127
Le XF et al. (2003) The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J Biol Chem 278: 23441–23450
Lane HA et al. (2001) Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling. Ann Oncol 12: 21–22
Nahta R et al. (2004) P27 (kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res 64: 3981–3986
Kute T et al. (2004) Development of Herceptin resistance in breast cancer cells. Cytometry A 57: 86–93
Agus DB et al. (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2: 127–137
Cho HS et al. (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421: 756–760
Franklin MC et al. (2004) Insights into ErbB signaling from the structure of the ErbB2–pertuzumab complex. Cancer Cell 5: 317–328
Nahta R et al. (2004) The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 64: 2343–2346
Batra JK et al. (1992) Recombinant anti-erbB-2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci USA 89: 5867–5871
Wels W et al. (1992) Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor. Cancer Res 52: 6310–6317
Rosenblum MG et al. (1999) Recombinant immunotoxins directed against the c-erb-2/HER2/neu oncogene product: in vitro cytotoxicity, pharmacokinetics, and in vivo efficacy studies in xenograft models. Clin Cancer Res 5: 865–874
Rosenblum MG et al. (2000) A novel recombinant fusion toxin targeting HER-2/NEU-over-expressing cells and containing human tumor necrosis factor. Int J Cancer 88: 267–273
Lyu MA and Rosenblum MG (2005) The immunocytokine scFv23/TNF sensitizes HER-2/neu-overexpressing SKBR-3 cells to tumor necrosis factor (TNF) via up-regulation of TNF receptor-1. Mol Cancer Ther 4: 1205–1213
Reiter Y et al. (1994) Cytotoxic and antitumor activity of a recombinant immunotoxin composed of disulfide-stabilized anti-Tac Fv fragment and truncated Pseudomonas exotoxin. Int J Cancer 58: 142–149
King CR et al. (1996) The performance of e23(Fv)PE, recombinant toxins targeting the erbB-2 protein. Semin Cancer Biol 7: 79–86
Rusnak DW et al. (2001) The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 61: 7196–7203
Allen LF et al. (2002) Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 29: 11–21
Wood ER et al. (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64: 6652–6659
Xia W et al. (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21: 6255–6263
Xia W et al. (2005) Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24: 6213–6221
Blackwell KL et al. (2004) Determining molecular phenotypes of metastatic breast cancer that respond to the small molecule inhibitor of ErbB1 and ErbB2, lapatinib (GW572016) [abstract]. Proc San Antonio Breast Cancer Symposium: a302
Burris HA III et al. (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23: 5305–5313
Konecny GE et al. (2006) Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66: 1630–1639
Camirand A et al. (2002) Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit 8: BR521–BR526
Cohen BD et al. (2005) Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11: 2063–2073
Garcia-Echeverria C et al. (2004) In vivo antitumor activity of NVP-AEW541—a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5: 231–239
Crul M et al. (2002) Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 38: 1615–1621
Van Ummersen L et al. (2004) A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 10: 7450–7456
Hidalgo M and Rowinsky EK (2000) The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19: 6680–6686
Chan S et al. (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23: 5314–5322
Zhang H and Burrows F (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82: 488–499
Yu D et al. (1990) Transcriptional repression of the neu protooncogene by the adenovirus 5 E1A gene products. Proc Natl Acad Sci USA 87: 4499–4503
Yu D et al. (1995) Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. Oncogene 11: 1383–1388
Hortobagyi GN et al. (2001) Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J Clin Oncol 19: 3422–3433
Knutson KL et al. (2002) Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369–377, results in short-lived peptide-specific immunity. Clin Cancer Res 8: 1014–1018
Bernhard H et al. (2002) Vaccination against HER-2/neu oncogenic protein. Endocr Relat Cancer 9: 33–44
Disis ML et al. (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20: 2624–2632
Piccart-Gebhart MJ et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 20: 1659–1672
Romand EH et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 20: 1673–1684
Cuello M et al. (2001) Down-regulation of the erbB-2 receptor by trastuzumab (Herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res 61: 4892–4900
Yen L et al. (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19: 3460–3469
Izumi Y et al. (2002) Tumour biology: Herceptin acts as an anti-angiogenic cocktail. Nature 416: 279–280
Molina MA et al. (2001) Trastuzumab (Herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells. Cancer Res 61: 4744–4749
Esteva FJ et al. (2002) Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20: 1800–1808
Pietras RJ et al. (1994) Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9: 1829–1838
Pietras RJ et al. (1998) Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17: 2235–2249
Pietras RJ et al. (1999) Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res 59: 1347–1355
Acknowledgements
The authors wish to acknowledge funding from the American Association for Cancer Research-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research (R Nahta), K23 CA82119 (FJ Esteva), the University Cancer Foundation Fund at the University of Texas MD Anderson Cancer Center (FJ Esteva, R Nahta), the Nellie B Connally Breast Cancer Research Fund for supporting the Breast Cancer Translational Research Laboratory at MD Anderson Cancer Center, and NIH Cancer Center Support Grant CA 16672-27.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
LA Liotta is a co-inventor on patents that describe technologies that are covered in this manuscript. By law, I am entitled to receive royalties on any license taken. EF Petricoin is an inventor on patents that describe technologies that are covered in this manuscript. By law, I am entitled to receive royalties on any license taken.
Rights and permissions
About this article
Cite this article
Nahta, R., Yu, D., Hung, MC. et al. Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Rev Clin Oncol 3, 269–280 (2006). https://doi.org/10.1038/ncponc0509
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncponc0509
This article is cited by
-
Novel HER2-targeted therapy to overcome trastuzumab resistance in HER2-amplified gastric cancer
Scientific Reports (2023)
-
Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation
British Journal of Cancer (2022)
-
Ensemble of nucleic acid absolute quantitation modules for copy number variation detection and RNA profiling
Nature Communications (2022)
-
Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells
Molecular Cancer (2022)
-
The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer
Cell Death & Disease (2021)