Non-small cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation

被引:189
作者
Das, Amit K.
Sato, Mitsuo
Story, Michael D.
Peyton, Michael
Graves, Robert
Redpath, Stella
Girard, Luc
Gazdar, Adi F.
Shay, Jerry W.
Minna, John D.
Nirodi, Chaitanya S.
机构
[1] Univ Texas, SW Med Ctr, Div Mol Radiat Biol, Dept Radiat Oncol, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Div Mol Radiat Biol, Dept Radiat Oncol, Dallas, TX 75390 USA
[3] Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA
[4] Univ Texas, SW Med Ctr, Simmons Canc Ctr, Dallas, TX 75390 USA
[5] Univ Texas, SW Med Ctr, Dept Cell Biol, Dallas, TX 75390 USA
[6] Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75390 USA
[7] Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA
[8] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[9] GE Healthcare, Piscataway, NJ USA
关键词
D O I
10.1158/0008-5472.CAN-06-2627
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tvrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the Delta E746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective ER-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.
引用
收藏
页码:9601 / 9608
页数:8
相关论文
共 37 条
[1]  
Amann J, 2005, CANCER RES, V65, P226
[2]   Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474 [J].
Arao, T ;
Fukumoto, H ;
Takeda, M ;
Tamura, T ;
Saijo, N ;
Nishio, K .
CANCER RESEARCH, 2004, 64 (24) :9101-9104
[3]   Chk1 and Chk2 kinases in checkpoint control and cancer [J].
Bartek, J ;
Lukas, J .
CANCER CELL, 2003, 3 (05) :421-429
[4]   Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials [J].
Bell, DW ;
Lynch, TJ ;
Haserlat, SM ;
Harris, PL ;
Okimoto, RA ;
Brannigan, BW ;
Sgroi, DC ;
Muir, B ;
Riemenschneider, MJ ;
Iacona, RB ;
Krebs, AD ;
Johnson, DH ;
Giaccone, G ;
Herbst, RS ;
Manegold, C ;
Fukuoka, M ;
Kris, MG ;
Baselga, J ;
Ochs, JS ;
Haber, DA .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (31) :8081-8092
[5]  
Bergqvist AS, 2001, ANTICANCER RES, V21, P3853
[6]  
Burdak-Rothkamm S, 2005, STRAHLENTHER ONKOL, V181, P197, DOI 10.1007/s00066-005-1319-5
[7]   Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase [J].
Dittmann, K ;
Mayer, C ;
Fehrenbacher, B ;
Schaller, M ;
Raju, U ;
Milas, L ;
Chen, DJ ;
Kehlbach, R ;
Rodemann, HP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (35) :31182-31189
[8]   Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity [J].
Dittmann, K ;
Mayer, C ;
Rodemann, HP .
RADIOTHERAPY AND ONCOLOGY, 2005, 76 (02) :157-161
[9]   Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib [J].
Eberhard, DA ;
Johnson, BE ;
Amler, LC ;
Goddard, AD ;
Heldens, SL ;
Herbst, RS ;
Ince, WL ;
Jänne, PA ;
Januario, T ;
Johnson, DH ;
Klein, P ;
Miller, VA ;
Ostland, MA ;
Ramies, DA ;
Sebisanovic, D ;
Stinson, JA ;
Zhang, YR ;
Seshagiri, S ;
Hillan, KJ .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (25) :5900-5909
[10]   ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines [J].
Engelman, JA ;
Jänne, PA ;
Mermel, C ;
Pearlberg, J ;
Mukohara, T ;
Fleet, C ;
Cichowski, K ;
Johnson, BE ;
Cantley, LC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (10) :3788-3793