| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cancer Therapy: Clinical |
Authors' Affiliations: Departments of 1 Molecular Diagnostics, 2 Pathology, 3 Bioinformatics, 4 Molecular Biology, and 5 BioOncology, Genentech, Inc., South San Francisco, California
Requests for reprints: Lukas C. Amler, Molecular Diagnostics, Genentech, Inc., Mail Stop 33, 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-1152; E-mail: amler{at}gene.com.
Significant improvements in the outcome of non–small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. To discover biomarkers for the enrichment of patients who might benefit from treatment, a pharmacogenomic approach was used to identify gene signatures that may predict erlotinib activity using in vitro model systems. Erlotinib sensitivity in a panel of 42 NSCLC cell lines was determined by EGFR-mediated proliferative potential, EGFR mutations, and/or EGFR gene amplification, thus supporting an underlying biological mechanism of receptor activation. A strong multigene signature indicative of an epithelial to mesenchymal transition (EMT) was identified as a determinant of insensitivity to erlotinib through both supervised and unsupervised gene expression approaches. This observation was further supported by expression analysis of classic EMT marker proteins, including E-cadherin and vimentin. To investigate the clinical relevance of these findings, we examined expression of the epithelial marker E-cadherin by immunohistochemistry on primary tumor samples from subjects enrolled in a randomized NSCLC clinical trial in which erlotinib in combination with chemotherapy previously failed to show clinical activity. The majority (75%) of the 87 subjects tested showed strong E-cadherin staining and exhibited a significantly longer time to progression (hazard ratio, 0.37; log rank P = 0.0028) and a nonsignificant trend toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy alone. These data support a potential role for EMT as a determinant of EGFR activity in NSCLC tumor cells and E-cadherin expression as a novel biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients.
This article has been cited by other articles:
|
|
 |
|
  G. Giaccone and P. A. Zucali Src as a potential therapeutic target in non-small-cell lung cancer Ann. Onc., July 1, 2008; 19(7): 1219 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. N. Fleming, M. Hogben, S. Frame, S. J. McClue, and S. R. Green Synergistic Inhibition of ErbB Signaling by Combined Treatment with Seliciclib and ErbB-Targeting Agents Clin. Cancer Res., July 1, 2008; 14(13): 4326 - 4335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Zucali, M. G. Ruiz, E. Giovannetti, A. Destro, M. Varella-Garcia, K. Floor, G. L. Ceresoli, J. A. Rodriguez, I. Garassino, P. Comoglio, et al. Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors Ann. Onc., May 7, 2008; (2008) mdn240v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Fuchs, T. Fujii, J. D. Dorfman, J. M. Goodwin, A. X. Zhu, M. Lanuti, and K. K. Tanabe Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells Cancer Res., April 1, 2008; 68(7): 2391 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Black, G. A. Brown, T. Inamoto, M. Shrader, A. Arora, A. O. Siefker-Radtke, L. Adam, D. Theodorescu, X. Wu, M. F. Munsell, et al. Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells Clin. Cancer Res., March 1, 2008; 14(5): 1478 - 1486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guix, N. de Matos Granja, I. Meszoely, T. B. Adkins, B. M. Wieman, K. E. Frierson, V. Sanchez, M. E. Sanders, A. M. Grau, I. A. Mayer, et al. Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor-Positive Breast Cancers J. Clin. Oncol., February 20, 2008; 26(6): 897 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shintani, M. Maeda, N. Chaika, K. R. Johnson, and M. J. Wheelock Collagen I Promotes Epithelial-to-Mesenchymal Transition in Lung Cancer Cells via Transforming Growth Factor Signaling Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 95 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Javle, J. F. Gibbs, K. K. Iwata, Y. Pak, P. Rutledge, J. Yu, J. D. Black, D. Tan, and T. Khoury Epithelial-Mesenchymal Transition (EMT) and Activated Extracellular Signal-regulated Kinase (p-Erk) in Surgically Resected Pancreatic Cancer Ann. Surg. Oncol., December 1, 2007; 14(12): 3527 - 3533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chu, H. Xu, T. J. Ferro, and P. X. Rivera Poly(ADP-ribose) polymerase-1 regulates vimentin expression in lung cancer cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1127 - L1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Minna, L. Girard, and Y. Xie Tumor mRNA Expression Profiles Predict Responses to Chemotherapy J. Clin. Oncol., October 1, 2007; 25(28): 4329 - 4336. [Full Text] [PDF]
|
|
|
|
|
|
H.-W. Lo, S.-C. Hsu, W. Xia, X. Cao, J.-Y. Shih, Y. Wei, J. L. Abbruzzese, G. N. Hortobagyi, and M.-C. Hung Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression Cancer Res., October 1, 2007; 67(19): 9066 - 9076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Wang, C. Sloss, X. Zhang, S. W. Lee, and J. C. Cusack Membrane-Bound Heparin-Binding Epidermal Growth Factor Like Growth Factor Regulates E-Cadherin Expression in Pancreatic Carcinoma Cells Cancer Res., September 15, 2007; 67(18): 8486 - 8493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rosano, V. Di Castro, F. Spinella, G. Tortora, M. R. Nicotra, P. G. Natali, and A. Bagnato Combined Targeting of Endothelin A Receptor and Epidermal Growth Factor Receptor in Ovarian Cancer Shows Enhanced Antitumor Activity Cancer Res., July 1, 2007; 67(13): 6351 - 6359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yamasaki, M. J. Johansen, D. Zhang, S. Krishnamurthy, E. Felix, C. Bartholomeusz, R. J. Aguilar, K. Kurisu, G. B. Mills, G. N. Hortobagyi, et al. Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt Cancer Res., June 15, 2007; 67(12): 5779 - 5788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Frederick, B. A. Helfrich, C. D. Coldren, D. Zheng, D. Chan, P. A. Bunn Jr., and D. Raben Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma Mol. Cancer Ther., June 1, 2007; 6(6): 1683 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schaefer, L. Shao, K. Totpal, and R. W. Akita Erlotinib Directly Inhibits HER2 Kinase Activation and Downstream Signaling Events in Intact Cells Lacking Epidermal Growth Factor Receptor Expression Cancer Res., February 1, 2007; 67(3): 1228 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buck, A. Eyzaguirre, S. Barr, S. Thompson, R. Sennello, D. Young, K. K. Iwata, N. W. Gibson, P. Cagnoni, and J. D. Haley Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition Mol. Cancer Ther., February 1, 2007; 6(2): 532 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shrader, M. S. Pino, G. Brown, P. Black, L. Adam, M. Bar-Eli, C. P.N. Dinney, and D. J. McConkey Molecular correlates of gefitinib responsiveness in human bladder cancer cells Mol. Cancer Ther., January 1, 2007; 6(1): 277 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Rosell, M. Taron, N. Reguart, D. Isla, and T. Moran Epidermal Growth Factor Receptor Activation: How Exon 19 and 21 Mutations Changed Our Understanding of the Pathway Clin. Cancer Res., December 15, 2006; 12(24): 7222 - 7231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Helfrich, D. Raben, M. Varella-Garcia, D. Gustafson, D. C. Chan, L. Bemis, C. Coldren, A. Baron, C. Zeng, W. A. Franklin, et al. Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels Clin. Cancer Res., December 1, 2006; 12(23): 7117 - 7125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Carey, A. J. Garton, M. S. Romero, J. Kahler, S. Thomson, S. Ross, F. Park, J. D. Haley, N. Gibson, and M. X. Sliwkowski Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib Cancer Res., August 15, 2006; 66(16): 8163 - 8171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Chung, J. S. Parker, K. Ely, J. Carter, Y. Yi, B. A. Murphy, K. K. Ang, A. K. El-Naggar, A. M. Zanation, A. J. Cmelak, et al. Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-{kappa}B Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma Cancer Res., August 15, 2006; 66(16): 8210 - 8218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Coldren, B. A. Helfrich, S. E. Witta, M. Sugita, R. Lapadat, C. Zeng, A. Baron, W. A. Franklin, F. R. Hirsch, M. W. Geraci, et al. Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non-Small Cell Lung Cancer Cell Lines Mol. Cancer Res., August 1, 2006; 4(8): 521 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E.W. Cohen Role of Epidermal Growth Factor Receptor Pathway-Targeted Therapy in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., June 10, 2006; 24(17): 2659 - 2665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dohadwala, S.-C. Yang, J. Luo, S. Sharma, R. K. Batra, M. Huang, Y. Lin, L. Goodglick, K. Krysan, M. C. Fishbein, et al. Cyclooxygenase-2-Dependent Regulation of E-Cadherin: Prostaglandin E2 Induces Transcriptional Repressors ZEB1 and Snail in Non-Small Cell Lung Cancer. Cancer Res., May 15, 2006; 66(10): 5338 - 5345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Cardiff Epithelial to Mesenchymal Transition Tumors: Fallacious or Snail's Pace? Clin. Cancer Res., December 15, 2005; 11(24): 8534 - 8537. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Cell Growth & Differentiation |
