A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer

被引:292
作者
Xia, Wenle
Bacus, Sarah
Hegde, Priti
Husain, Intisar
Strum, Jay
Liu, Leihua
Paulazzo, Georgina
Lyass, Ljuba
Trusk, Patricia
Hill, Jason
Harris, Jennifer
Spector, Neil L. [1 ]
机构
[1] GlaxoSmithKline, Dept Oncol Biol, Res Triangle Pk, NC 27709 USA
[2] GlaxoSmithKline, Dept Genom & Proteom Sci, Res Triangle Pk, NC 27709 USA
[3] Targeted Mol Diagnost, Westmont, IL 60559 USA
关键词
estrogen receptor; lapatinib; resistance;
D O I
10.1073/pnas.0602468103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy of this class of cancer therapeutics. Little is known about the mechanism(s) of acquired resistance to these agents. Here we establish a model of acquired resistance to N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}6-[5-({[2 (methylsulfonyl)ethyllamino}methyl)-2-furyl]-4-quinazolinamine (lapatinib), an inhibitor of ErbB2 and ErbB1 tyrosine kinases by chronically exposing lapatinib-sensitive ErbB2-overexpressing breast cancer cells to lapatinib, simulating the clinic where lapatinib is administered on a daily chronic basis. Analysis of baseline gene expression in acquired lapatinib-resistant and parental cells indicates estrogen receptor (ER) signaling involvement in the development of resistance. Using gene interference, we confirm that acquired resistance to lapatinib is mediated by a switch in cell survival dependence and regulation of a key antiapoptotic mediator from ErbB2 alone to codependence upon ER and ErbB2 rather than loss of ErbB2 expression or insensitivity of ErbB2 signaling to lapatinib. Increased ER signaling in response to lapatinib is enhanced by the activation of factors facilitating the transcriptional activity of ER, notably FOXO3a and caveolin-1. Importantly, we confirm that lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving lapatinib therapy. These findings provided the rationale for preventing the development of acquired resistance by simultaneously inhibiting both ER and ErbB2 signaling pathways. Establishing clinically relevant models of acquired resistance to ErbB2 kinase inhibitors will enhance therapeutic strategies to improve clinical outcomes for patients with ErbB2-overexpressing breast cancers.
引用
收藏
页码:7795 / 7800
页数:6
相关论文
共 37 条
  • [1] A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma
    Ambrosini, G
    Adida, C
    Altieri, DC
    [J]. NATURE MEDICINE, 1997, 3 (08) : 917 - 921
  • [2] HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: A southwest oncology group study
    Arpino, G
    Green, SJ
    Allred, DC
    Lew, D
    Martino, S
    Osborne, CK
    Elledge, RM
    [J]. CLINICAL CANCER RESEARCH, 2004, 10 (17) : 5670 - 5676
  • [3] AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival
    Bacus, SS
    Altomare, DA
    Lyass, L
    Chin, DM
    Farrell, MP
    Gurova, K
    Gudkov, A
    Testa, JR
    [J]. ONCOGENE, 2002, 21 (22) : 3532 - 3540
  • [4] Studies of the fine structure of the object 1803+784
    Britzen, S
    Witzel, A
    Krichbaum, TP
    MacSlow, T
    Matveyenko, LI
    [J]. ASTRONOMY LETTERS-A JOURNAL OF ASTRONOMY AND SPACE ASTROPHYSICS, 2001, 27 (01): : 1 - 14
  • [5] 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
    Burris, HA
    Hurwitz, HI
    Dees, EC
    Dowlati, A
    Blackwell, KL
    O'Neil, B
    Marcom, PK
    Ellis, MJ
    Overmoyer, B
    Jones, SF
    Harris, JL
    Smith, DA
    Koch, KM
    Stead, A
    Mangum, S
    Spector, NL
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (23) : 5305 - 5313
  • [6] Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease
    Cobleigh, MA
    Vogel, CL
    Tripathy, D
    Robert, NJ
    Scholl, S
    Fehrenbacher, L
    Wolter, JM
    Paton, V
    Shak, S
    Lieberman, G
    Slamon, DJ
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (09) : 2639 - 2648
  • [7] Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2
    Cockerill, S
    Stubberfield, C
    Stables, J
    Carter, M
    Guntrip, S
    Smith, K
    McKeown, S
    Shaw, R
    Topley, P
    Thomsen, L
    Affleck, K
    Jowett, A
    Hayes, D
    Willson, M
    Woollard, P
    Spalding, D
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (11) : 1401 - 1405
  • [8] Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway
    Guo, SQ
    Sonenshein, GE
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (19) : 8681 - 8690
  • [9] Hortobagyi GN, 1999, SEMIN ONCOL, V26, P11
  • [10] Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells
    Keen, JC
    Garrett-Mayer, E
    Petit, C
    Mack, KM
    Manning, J
    Herman, JG
    Davidson, NE
    [J]. CANCER BIOLOGY & THERAPY, 2004, 3 (12) : 1304 - 1312