Mechanisms of lapatinib resistance in HER2-driven breast cancer

Cancer Treatment Reviews

Volumn 41, Issue 10, 2015, Pages 877-883

  D'Amato, Valentina ^a   Raimondo, Lucia ^a   Formisano, Luigi ^a   Giuliano, Mario ^a   De Placido, Sabino ^a   Rosa, Roberta ^a   Bianco, Roberto ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Breast cancer; ErbB2 HER2; Lapatinib; Resistance

Indexed keywords

AXL KINASE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ESTROGEN RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE 6; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; ERBB2 PROTEIN, HUMAN; LAPATINIB; PHOSPHOTRANSFERASE; QUINAZOLINE DERIVATIVE;

ARTICLE; BREAST CANCER; CANCER PROGNOSIS; CELL PROLIFERATION; CELL SURVIVAL; DRUG RESISTANCE; ENZYME ACTIVATION; GENE AMPLIFICATION; HUMAN; LIGAND INDUCED RESCUE; MOLECULAR BIOLOGY; MOLECULAR DYNAMICS; MUTATIONAL ANALYSIS; PHENOTYPE; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; TK DOMAIN; TUMOR ESCAPE; BREAST NEOPLASMS; FEMALE; GENETICS; METABOLISM; MUTATION;

ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; DRUG RESISTANCE, NEOPLASM; FEMALE; GENE AMPLIFICATION; HUMANS; MUTATION; PHOSPHOTRANSFERASES; PROTEIN-TYROSINE KINASES; QUINAZOLINES; RECEPTOR, ERBB-2; RECEPTORS, ESTROGEN;

EID: 84958939052     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2015.08.001     Document Type: Review

References (63)

1. Izar B, Rotow J, Gainor J, Clark J, Chabner B. Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev 2013;65:1351-95.
2. Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984;312:513-6.
3. Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995;10:1813-21.
4. Carey LA. Breast cancer: HER2 - a good addiction. Nat Rev Clin Oncol 2012;9:196-7.
5. Berger MS, Locher GW, Saurer S, Gullick WJ, Waterfield MD, Groner B, et al. Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res 1988;48:1238-43.
6. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92.
7. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer Jr CE, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014;32:3744-52.
8. Medina PJ, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 2008;30:1426-47.
9. Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R, et al. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 2008;13:1114-9.
10. Jagiello-Gruszfeld A, Tjulandin S, Dobrovolskaya N, Manikhas A, Pienkowski T, DeSilvio M, et al. A single-arm phase II trial of first-line paclitaxel in combination with lapatinib in HER2-overexpressing metastatic breast cancer. Oncology 2010;79:129-35.
11. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers - role of estrogen receptor and HER2 reactivation. Breast Cancer Res 2011;13:R121.
12. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007;445:437-41.
13. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sánchez V, Chakrabarty A, 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;108:5021-6.
14. Jiang Y, Zou L, Lu WQ, Zhang Y, Shen AG. Foxo3a expression is a prognostic marker in breast cancer. PLoS ONE 2013;8:e70746.
15. Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008;7:504-16.
16. Shattuck DL, Miller JK, Carraway 3rd KL, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 2008;68:1471-7.
17. Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer Res 2009;15:7479-91.
18. Corso S, Giordano S. Cell-autonomous and non-cell-autonomous mechanisms of HGF/MET-driven resistance to targeted therapies: from basic research to a clinical perspective. Cancer Discov 2013;3:978-92.
19. Chen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther 2012;11:660-9.
20. Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res 2008;68:1905-15.
21. Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 2007;26:3909-19.
22. Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett 2008;268:314-24.
23. Macleod K, Mullen P, Sewell J, Rabiasz G, Lawrie S, Miller E, et al. Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res 2005;65:6789-800.
24. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 2012;44:852-60.
25. Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871-8.
26. Brown KK, Toker A. The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000 Prime Rep 2015; 7: 13.
27. Hegde PS, Rusnak D, Bertiaux M, Alligood K, Strum J, Gagnon R, et al. Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther 2007;6:1629-40.
28. Elster N, Cremona M, Morgan C, Toomey S, Carr A, O'Grady A, et al. A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2- targeted therapies trastuzumab and lapatinib. Breast Cancer Res Treat 2015;149:373-83.
29. Brady SW, Zhang J, Tsai MH, Yu D. PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition. Cancer Biol Ther 2015;16:402-11.
30. Vazquez-Martin A, Oliveras-Ferraros C, Colomer R, Brunet J, Menendez JA. Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb) in human breast carcinoma cells. Ann Oncol 2008;19:1097-109.
31. Roskoski Jr R. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res 2015;94:9-25.
32. Elsberger B. Translational evidence on the role of Src kinase and activated Src kinase in invasive breast cancer. Crit Rev Oncol Hematol 2014;89:343-51.
33. Rexer BN, Ham AJ. Phosphoproteomic mass spectrometry profiling links Src family Kinases to escape from HER2 tyrosine kinase inhibition. Oncogene 2011;30(4163):4174.
34. Formisano L, Nappi L, Rosa R, Marciano R, D'Amato C, D'Amato V, et al. Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res 2014;16: R45.
35. Xiang B, Chatti K, Qiu H, Lakshmi B, Krasnitz A, Hicks J, et al. Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc Natl Acad Sci U S A 2008;105:12463-8.
36. Park SH, Ito K, Olcott W, Katsyv I, Halstead-Nussloch G, Irie HY. PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2+ breast cancer cells by inducing Bim. Breast Cancer Res 2015;17:86.
37. Stuhlmiller TJ, Miller SM, Zawistowski JS, Nakamura K, Beltran AS, Duncan JS, et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2- positive breast cancer by targeting BET family bromodomains. Cell Rep 2015;11:390-404.
38. Moody SE, Schinzel AC, Singh S, Izzo F, Strickland MR, Luo L, et al. PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling. Oncogene 2015;34:2061-71.
39. Zhang W, Huang P. Cancer-stromal interactions: role in cell survival, metabolism and drug sensitivity. Cancer Biol Ther 2011;11:150-6.
40. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012;487:505-9.
41. Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinibmediated growth inhibition of HER2-amplified cancer cells. Cancer Sci 2013;104:1618-25.
42. Xia W, Petricoin 3rd EF, Zhao S, Liu L, Osada T, Cheng Q, et al. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res 2013;15:R85.
43. Fagan Dedra H, Yee Douglas. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008;13:423-9.
44. Schiff R, Massarweh SA, Shou J, Bharwani L, Arpino G, Rimawi M, et al. Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators. Cancer Chemother Pharmacol 2005;56:10-20.
45. Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A 2006;103:7795-800.
46. Giuliano M, Hu H, Wang YC, Fu X, Nardone A, Herrera S, et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin Cancer Res 2015 [Epub ahead of print].
47. Cohen EE, Lingen MW, Martin LE, Harris PL, Brannigan BW, Haserlat SM, et al. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clin Cancer Res 2005;11:8105-8.
48. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525-6.
49. Trowe T, Boukouvala S, Calkins K, Cutler Jr RE, Fong R, Funke R, et al. EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. Clin Cancer Res 2008;14:2465-75.
50. Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, et al. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res 2007;13:3713-23.
51. Harris LN, You F, Schnitt SJ, Witkiewicz A, Lu X, Sgroi D, et al. Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res 2007;13:1198-207.
52. Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A 2011;108:3761-6.
53. Wetterskog D, Shiu KK, Chong I, Meijer T, Mackay A, Lambros M, et al. Identification of novel determinants of resistance to lapatinib in ERBB2- amplified cancers. Oncogene 2014;33:966-76.
54. Hu WH, Pendergast JS, Mo XM, Brambilla R, Bracchi-Ricard V, Li F, et al. NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. J Biol Chem 2005;280:29233-41.
55. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724-34.
56. A study to evaluate RO5479599 in combination with perjeta (pertuzumab) and paclitaxel in patients with metastatic breast cancer expressing HER3 & HER2 protein. [Available from: (accessed 2015 Jul 28)].
57. Study of foretinib in combinationwith lapatinib in patients withmetastatic breast cancer. [Available from: (accessed 2015 Jul 28)].
58. Wilks ST. Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast 2015.
59. A phase IB trialwith OTX015, a smallmolecule inhibitor of the bromodomain and extra-terminal (BET) proteins, in patients with selected advanced solid tumors. [Available from: (accessed 2015 Jul 28)].
60. MM-111 in combination with herceptin in patients with advanced Her2 amplified, heregulin positive breast cancer. [Available from: (accessed 2015 Jul 28)].
61. Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 2013;31:1726-31.
62. Study of the combination of KD019 and trastuzumab in subjects with HER2- positive metastatic breast cancer. [Available from: (accessed 2015 Jul 28)].
63. Phase II study of curcumin vs placebo for chemotherapy-treated breast cancer patients undergoing radiotherapy. [Available from: (accessed 2015 Jul 28)].