| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 Oxford University Press
ARTICLE |
Differential Effects of Gefitinib and Cetuximab on Non–small-cell Lung Cancers Bearing Epidermal Growth Factor Receptor Mutations
Affiliations of authors: Lowe Center for Thoracic Oncology (TM, BEJ, PAJ) and Department of Medical Oncology (TM, JAE, JP, BEJ, PAJ), Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital, Boston, MA (TM, JAE, BEJ, PAJ); Massachusetts General Hospital, Boston, MA (BYY); Harvard Medical School, Boston, MA (TM, JAE, BYY, BEJ, PAJ); Department of Systems Biology, Harvard Medical School, and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA (JAE, LCC); Department of Medicine, Indiana University, Indianapolis, IN (NHH); Biostatistics Center, Massachusetts General Hospital, Boston, MA (BYY); Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (SK, BH, DGT); Department of Pathology, Brigham and Women's Hospital, Boston, MA (NL); Ireland Cancer Center, University Hospitals of Cleveland, Case School of Medicine, Cleveland, OH (BH); Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ (ZT)
Correspondence to: Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D1234, 44 Binney St., Boston, MA 02115 (e-mail: pjanne{at}partners.org).
Background: Many patients with non–small-cell lung cancer (NSCLC) who achieve radiographic responses to treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib have somatic mutations in the EGFR tyrosine kinase domain. However, little is known about the efficacy of cetuximab, an antibody against the EGFR extracellular domain, in EGFR mutant NSCLC. Methods: NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) were treated with various dilutions of gefitinib or cetuximab relative to maximal achievable serum concentration. Cell growth was analyzed by the MTS assay, with differences between dose–response curves analyzed nonparametrically. Apoptosis was analyzed by propidium iodide staining and immunoblotting for PARP. Phosphorylation of EGFR and the downstream signaling components ERK1/2 and Akt were analyzed by immunoblotting. Statistical tests were two-sided. Results: Growth of NSCLC lines with wild-type EGFR was slightly (A549 and H441) or moderately (H1666) inhibited by gefitinib and cetuximab, and the effects of the two agents were similar. Both agents also induced no (H441) or moderate (H1666) apoptosis in NSCLC cells with wild-type EGFR. By contrast, gefitinib was statistically significantly more effective than cetuximab at inhibiting growth of EGFR mutant cells (H3255: P = .003, DFCILU-011: P = .011, and PC-9: P = .003), and gefitinib-treated EGFR mutant cells had higher levels of apoptosis than cetuximab-treated cells (mean fold increase in apoptosis by 1 µM of gefitinib and 10 µg/mL of cetuximab relative to control, H3255: 8.3 [95% confidence interval {CI} = 4.8 to 11.8] and 2.1 [95% CI = 2.0 to 2.2], respectively, P = .025; DFCILU-011: 5.7 [95% CI = 5.1 to 6.3] and. 0.9 [95% CI = 0.3 to 1.5], respectively, P<.001). Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect. Both gefitinib and cetuximab inhibited the growth of HCC827 cells, but gefitinib inhibited growth to a greater extent (P = .003). Conclusions: EGFR mutations in NSCLC cells are associated with sensitivity to gefitinib but not to cetuximab.
CiteULike 
Connotea 
Del.icio.us What's this?
Editorial about this Article
- Gefitinib Versus Cetuximab in Lung Cancer: Round One
- John D. Minna, Michael J. Peyton, and Adi F. Gazdar
J Natl Cancer Inst 2005 97: 1168-1169.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
|
|
 |
|
  L. M. Sholl, B. Y. Yeap, A. J. Iafrate, A. J. Holmes-Tisch, Y.-P. Chou, M.-T. Wu, Y.-G. Goan, L. Su, E. Benedettini, J. Yu, et al. Lung Adenocarcinoma with EGFR Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers Cancer Res., November 1, 2009; 69(21): 8341 - 8348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Freeman, T. Bush, S. Ogbagabriel, B. Belmontes, T. Juan, C. Plewa, G. Van, C. Johnson, and R. Radinsky Activity of panitumumab alone or with chemotherapy in non-small cell lung carcinoma cell lines expressing mutant epidermal growth factor receptor Mol. Cancer Ther., June 1, 2009; 8(6): 1536 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gridelli, P. Maione, M. L. Ferrara, and A. Rossi Cetuximab and Other Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in the Treatment of Non-Small Cell Lung Cancer Oncologist, June 1, 2009; 14(6): 601 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Naumov, M. B. Nilsson, T. Cascone, A. Briggs, O. Straume, L. A. Akslen, E. Lifshits, L. A. Byers, L. Xu, H.-k. Wu, et al. Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance Clin. Cancer Res., May 15, 2009; 15(10): 3484 - 3494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. KATAYAMA, K. SHIBATA, J. MITSUHASHI, K. NOGUCHI, and Y. SUGIMOTO Pharmacological Interplay between Breast Cancer Resistance Protein and Gefitinib in Epidermal Growth Factor Receptor Signaling Anticancer Res, April 1, 2009; 29(4): 1059 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Pernas, C. T. Allen, M. E. Winters, B. Yan, J. Friedman, B. Dabir, K. Saigal, G. S. Mundinger, X. Xu, J. C. Morris, et al. Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer Clin. Cancer Res., April 1, 2009; 15(7): 2361 - 2372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Schittenhelm, C. Kollmannsberger, K. Oechsle, A. Harlow, J. Morich, F. Honecker, R. Kurek, S. Storkel, L. Kanz, C. L. Corless, et al. Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer Mol. Cancer Ther., March 1, 2009; 8(3): 481 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Memon, S. Jakobsen, F. Dagnaes-Hansen, B. S. Sorensen, S. Keiding, and E. Nexo Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts Cancer Res., February 1, 2009; 69(3): 873 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okabe, I. Okamoto, S. Tsukioka, J. Uchida, E. Hatashita, Y. Yamada, T. Yoshida, K. Nishio, M. Fukuoka, P. A. Janne, et al. Addition of S-1 to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Overcomes Gefitinib Resistance in Non-small cell Lung Cancer Cell Lines with MET Amplification Clin. Cancer Res., February 1, 2009; 15(3): 907 - 913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yonesaka, K. Zejnullahu, N. Lindeman, A. J. Homes, D. M. Jackman, F. Zhao, A. M. Rogers, B. E. Johnson, and P. A. Janne Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers Clin. Cancer Res., November 1, 2008; 14(21): 6963 - 6973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. R. Hirsch, R. S. Herbst, C. Olsen, K. Chansky, J. Crowley, K. Kelly, W. A. Franklin, P. A. Bunn Jr, M. Varella-Garcia, and D. R. Gandara Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non-Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy J. Clin. Oncol., July 10, 2008; 26(20): 3351 - 3357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Koivunen, C. Mermel, K. Zejnullahu, C. Murphy, E. Lifshits, A. J. Holmes, H. G. Choi, J. Kim, D. Chiang, R. Thomas, et al. EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer Clin. Cancer Res., July 1, 2008; 14(13): 4275 - 4283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Engelman and P. A. Janne Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Clin. Cancer Res., May 15, 2008; 14(10): 2895 - 2899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cappuzzo, G. Finocchiaro, E. Rossi, P.A. Janne, C. Carnaghi, C. Calandri, K. Bencardino, C. Ligorio, F. Ciardiello, T. Pressiani, et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients Ann. Onc., April 1, 2008; 19(4): 717 - 723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations J. Immunol., March 15, 2008; 180(6): 4338 - 4345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ciardiello and G. Tortora EGFR Antagonists in Cancer Treatment N. Engl. J. Med., March 13, 2008; 358(11): 1160 - 1174. [Full Text] [PDF]
|
|
|
|
|
|
H.-P. Kim, S.-W. Han, S.-H. Kim, S.-A. Im, D.-Y. Oh, Y.-J. Bang, and T.-Y. Kim Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells Mol. Cancer Ther., March 1, 2008; 7(3): 607 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Rosell, G. Robinet, A. Szczesna, R. Ramlau, M. Constenla, B. C. Mennecier, W. Pfeifer, K. J. O'Byrne, T. Welte, R. Kolb, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer Ann. Onc., February 1, 2008; 19(2): 362 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Engelman, K. Zejnullahu, C.-M. Gale, E. Lifshits, A. J. Gonzales, T. Shimamura, F. Zhao, P. W. Vincent, G. N. Naumov, J. E. Bradner, et al. PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib Cancer Res., December 15, 2007; 67(24): 11924 - 11932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, X. Wu, W. Zhang, R. C. Montenegro, D. L. Fackenthal, J. A. Spitz, L. M. Huff, F. Innocenti, S. Das, E. H. Cook, Jr., et al. Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines Clin. Cancer Res., November 15, 2007; 13(22): 6788 - 6795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Roda, T. Joshi, J. P. Butchar, J. W. McAlees, A. Lehman, S. Tridandapani, and W. E. Carson III The Activation of Natural Killer Cell Effector Functions by Cetuximab-Coated, Epidermal Growth Factor Receptor Positive Tumor Cells is Enhanced By Cytokines Clin. Cancer Res., November 1, 2007; 13(21): 6419 - 6428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Doody, Y. Wang, S. N. Patel, C. Joynes, S. P. Lee, J. Gerlak, R. L. Rolser, Y. Li, P. Steiner, R. Bassi, et al. Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers Mol. Cancer Ther., October 1, 2007; 6(10): 2642 - 2651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Morgensztern and R. Govindan Is There a Role for Cetuximab in Non Small Cell Lung Cancer? Clin. Cancer Res., August 1, 2007; 13(15): 4602s - 4605s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I Chau, D Cunningham, T Hickish, A Massey, L Higgins, R Osborne, N Botwood, and A Swaisland Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study Ann. Onc., April 1, 2007; 18(4): 730 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okabe, I. Okamoto, K. Tamura, M. Terashima, T. Yoshida, T. Satoh, M. Takada, M. Fukuoka, and K. Nakagawa Differential Constitutive Activation of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Cells Bearing EGFR Gene Mutation and Amplification Cancer Res., March 1, 2007; 67(5): 2046 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Perez-Torres, M. Guix, A. Gonzalez, and C. L. Arteaga Epidermal Growth Factor Receptor (EGFR) Antibody Down-regulates Mutant Receptors and Inhibits Tumors Expressing EGFR Mutations J. Biol. Chem., December 29, 2006; 281(52): 40183 - 40192. [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]
|
|
|
|
|
|
G. J. Riely, K. A. Politi, V. A. Miller, and W. Pao Update on Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer Clin. Cancer Res., December 15, 2006; 12(24): 7232 - 7241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ono and M. Kuwano Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs Clin. Cancer Res., December 15, 2006; 12(24): 7242 - 7251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kobayashi, T. Shimamura, S. Monti, U. Steidl, C. J. Hetherington, A. M. Lowell, T. Golub, M. Meyerson, D. G. Tenen, G. I. Shapiro, et al. Transcriptional Profiling Identifies Cyclin D1 as a Critical Downstream Effector of Mutant Epidermal Growth Factor Receptor Signaling Cancer Res., December 1, 2006; 66(23): 11389 - 11398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hanna, R. Lilenbaum, R. Ansari, T. Lynch, R. Govindan, P. A. Janne, and P. Bonomi Phase II Trial of Cetuximab in Patients With Previously Treated Non Small-Cell Lung Cancer J. Clin. Oncol., November 20, 2006; 24(33): 5253 - 5258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Giaccone, M. Gallegos Ruiz, T. Le Chevalier, N. Thatcher, E. Smit, J. A. Rodriguez, P. Janne, D. Oulid-Aissa, and J.-C. Soria Erlotinib for Frontline Treatment of Advanced Non-Small Cell Lung Cancer: a Phase II Study. Clin. Cancer Res., October 15, 2006; 12(20): 6049 - 6055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Amicarelli, D. Adlerstein, E. Shehi, F. Wang, and G. M. Makrigiorgos Genotype-Specific Signal Generation Based on Digestion of 3-Way DNA Junctions: Application to KRAS Variation Detection Clin. Chem., October 1, 2006; 52(10): 1855 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Jackman, A. J. Holmes, N. Lindeman, P. Y. Wen, S. Kesari, A. M. Borras, C. Bailey, F. de Jong, P. A. Janne, and B. E. Johnson Response and Resistance in a Non-Small-Cell Lung Cancer Patient With an Epidermal Growth Factor Receptor Mutation and Leptomeningeal Metastases Treated With High-Dose Gefitinib J. Clin. Oncol., September 20, 2006; 24(27): 4517 - 4520. [Full Text] [PDF]
|
|
|
|
|
|
M. P. Cunningham, H. Thomas, Z. Fan, and H. Modjtahedi Responses of Human Colorectal Tumor Cells to Treatment with the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib. Cancer Res., August 1, 2006; 66(15): 7708 - 7715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Lilenbaum The evolving role of cetuximab in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4432s - 4435s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Jackman, B. Y. Yeap, L. V. Sequist, N. Lindeman, A. J. Holmes, V. A. Joshi, D. W. Bell, M. S. Huberman, B. Halmos, M. S. Rabin, et al. Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non-Small Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib. Clin. Cancer Res., July 1, 2006; 12(13): 3908 - 3914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Erjala, M. Sundvall, T. T. Junttila, N. Zhang, M. Savisalo, P. Mali, J. Kulmala, J. Pulkkinen, R. Grenman, and K. Elenius Signaling via ErbB2 and ErbB3 Associates with Resistance and Epidermal Growth Factor Receptor (EGFR) Amplification with Sensitivity to EGFR Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cells. Clin. Cancer Res., July 1, 2006; 12(13): 4103 - 4111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ramalingam and A. B. Sandler Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist, June 1, 2006; 11(6): 655 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wild, K. Fager, C. Flefleh, D. Kan, I. Inigo, S. Castaneda, F. Luo, A. Camuso, K. McGlinchey, and W. C. Rose Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels Mol. Cancer Ther., January 1, 2006; 5(1): 104 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. R. Hirsch and P. A. Bunn Jr Epidermal Growth Factor Receptor Inhibitors in Lung Cancer: Smaller or Larger Molecules, Selected or Unselected Populations? J. Clin. Oncol., December 20, 2005; 23(36): 9044 - 9047. [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Minna, M. J. Peyton, and A. F. Gazdar Gefitinib Versus Cetuximab in Lung Cancer: Round One J Natl Cancer Inst, August 17, 2005; 97(16): 1168 - 1169. [Full Text] [PDF]
|
|