Cancer Research Annual Meeting 2010 Sign up for Cancer Research eTOC's
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 Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shigematsu, H.
Right arrow Articles by Gazdar, A. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shigematsu, H.
Right arrow Articles by Gazdar, A. F.
[Cancer Research 65, 1642-1646, March 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas

Hisayuki Shigematsu1,9, Takao Takahashi1, Masaharu Nomura1, Kuntal Majmudar1, Makoto Suzuki5, Huei Lee6, Ignacio I. Wistuba7, Kwun M. Fong8, Shinichi Toyooka9, Nobuyoshi Shimizu9, Takehiko Fujisawa5, John D. Minna1,2,3 and Adi F. Gazdar1,4

1 Hamon Center for Therapeutic Oncology Research, Departments of 2 Internal Medicine, 3 Pharmacology, and 4 Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 5 Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; 6 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan; 7 Department of Pathology and Thoracic/Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 8 Prince Charles Hospital, Brisbane, Australia; and 9 Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

Requests for reprints: Adi F. Gazdar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas TX, 75390-8593. Phone: 214-648-4921; Fax: 214-648-4940; E-mail: adi.gazdar{at}utsouthwestern.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non–small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.

Key Words: HER2 • EGFR • KRAS • mutation • lung cancer


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Activating mutations of protein kinases contribute to the development of human cancers (1) and have led to the development of kinase inhibitors that target these oncogenic forms (2). The inhibitors include imatinib mesylate (Gleevec, STI571), a small molecule inhibitor of the Abl and KIT tyrosine kinases (TK) for patients with chronic myelogenous leukemia or gastrointestinal stromal tumors (3, 4), and gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774) inhibitors of epidermal growth factor receptor (EGFR) which are used for the treatment of non–small cell lung cancer (NSCLC). Recent reports of mutations in the TK domain of EGFR have generated considerable interest because they predict for sensitivity to gefitinib or erlotinib (5–7). The promising results of these TK inhibitors invoke the concept of "oncogene addiction," which hypothesizes that cancer cells are both transformed and physiologically dependent on activated oncogenes for their survival (8, 9). Thus, oncogenic activation of protein kinases including EGFR family members should be targets for cancer therapies.

HER2 (also known as NEU, EGFR2, or ERBB2) is one of the members of the EGFR family, which includes EGFR (or ERBB1), EGFR3 (or HER3/ERBB3) and EGFR4 (or HER4/ERBB4). Although the genes contain extracellular, transmembrane and intarcellular domains, the regions of greatest homology are the kinase domains contained within an intracellular domain. However, the genes have distinct properties: HER2 has strong kinase activity but has no identified ligand and ERBB3 lacks kinase activity due to substitutions in critical TK domain residues (10). All are capable of forming homodimers (with the possible exception of ERBB3) and heterodimers. EGFR and HER2 are dysregulated in many human cancers and play important roles in cancer development and progression (11). Overexpression of HER2 with amplification is found in a subset of breast and ovarian cancers and correlates with poor prognosis (12, 13). In lung cancers, overexpression of HER2 has been reported in about 20% (14–17) whereas gene amplification occurs less frequently than in breast cancers. Trastuzumab (Herceptin), a humanized monoclonal antibody that binds the extracellular domain of HER2, is effective for HER2 overexpressing breast cancer patients when used with other cytotoxic agents (18). By contrast, clinical trials using Trastuzumab in NSCLC patients have reported modest or disappointing clinical benefits (19–21). Recently, mutations of HER2 were reported in lung adenocarcinomas and offer the potential of additional therapy targeted at the altered protein (22). In this report, we searched for mutations of HER2 in a large number of primary lung tumors from four countries (Japan, Taiwan, the United States, and Australia). Because mutations in the EGRF gene target adenocarcinoma histology, female gender, never smoking status, and Oriental ethnicity (6, 7, 23), we determined whether there was a relationship between HER2 mutations and some or all of these factors. In addition, we correlated the mutation status of HER2, EGFR, and KRAS genes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Tumor Samples. A total of 671 primary NSCLCs were obtained from patients undergoing curative intent surgical resections from four countries (Table 1). All cases from Japan and Taiwan were of Oriental ethnicity. United States. cases comprised 137 Caucasian, 8 Hispanic, 6 African American, and 4 Oriental (ethnicity was not available for two cases). Australian cases were all Caucasian except for one Oriental. A total of 36 neuroendocrine lung tumors including bronchial carcinoids (n = 25) and large cell neuroendocrine carcinomas (n = 5) from the United States and SCLC (n = 6) from Japan were also studied. Eighty-five carcinomas arising at other sites (breast, n = 28; bladder, n = 15; prostate, n = 14; and colorectal cancer, n = 28) were obtained from the hospitals affiliated with the University of Texas Southwestern Medical Center. Institutional Review Board permission and informed consent were obtained at each collection site. Clinical information including gender, age, histology, clinical stage, and smoking history were available. Clinical staging was based on the revised International System for Staging Lung Cancer (24). We also studied 80 NSCLC cell lines established by us (25) except for NCI-H3255 which was initiated by and obtained from Dr. Bruce Johnson (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; ref. 26). The list of cell lines studied and their mutational status may be obtained from the senior author.


View this table:
[in this window]
[in a new window]

  		Table 1. KRAS, EGFR, and HER2 mutation in resected NSCLC

 
DNA Extraction and Sequencing of HER2, EGFR, and KRAS. Genomic DNA was obtained from primary tumors and cell lines by overnight digestion with SDS and proteinase K (Life Technologies, Inc., Rockville, MD) at 37C followed by standard phenol-chloroform (1:1) extraction and ethanol precipitation.

The intron-based PCR primer sequences for seven examined exons of the entire HER2 TK domains were as follows (forward and reverse, respectively): Exon 18 (5'-GTGAAGTCCTCCCAGCCCGC-3' and 5'-CTCCCATCAGAACTGCCGACC-3'), Exon 19 (5'-TGGAGGACAAGTAATGATCTCCTGG-3' and 5'-AAGAGAGACCAGAGCCCAGACCTG-3'), Exon 20 (5'-GCCATGGCTGTGGTTTGTGATGG-3' and 5'-ATCCTAGCCCCTTGTGGACATAGG-3'), Exon 21 (5'-GGACTCTTGCTGGGCATGTGG-3' and 5'-CCACTCAGAGTTCTCCCATGG-3'), Exon 22 (5'-CCATGGGAGAACTCTGAGTGG-3' and 5'-TCCCTTCACATGCTGAGGTGG-3'), Exon 23 (5'-AGACTCCTGAGCAGAACCTCTG-3' and 5'-AGCCAGCACAGCTCAGCCAC-3'), and Exon 24 (5'-ACTGTCTAGACCAGACTGGAGG-3' and 5'-GAGGGTGCTCTTAGCCACAGG-3'). All PCRs were carried out in 25-µL volume containing 100 ng of genomic DNA using HotStarTaq DNA polymerase (QIAGEN Inc., Valencia, CA). DNA was amplified for 32 to 34 cycles at 95°C for 30 seconds, 62°C to 68°C for 30 seconds, and 72°C for 30 seconds followed by 7 minutes extension at 72°C. All PCR products were incubated using exonuclease I and shrimp alkaline phosphatase (Amersham Biosciences Co., Piscataway, NJ) and sequenced directly using Applied Biosystems PRISM dye terminator cycle sequencing method (Perkin-Elmer Co., Foster City, CA). All sequence variants were confirmed by independent PCR amplifications and sequenced in both directions.

EGFR (exons 18-21) and KRAS (codons 12 and 13) mutation status were determined using the intron-based PCR primers as described previously (23). The EGFR and RAS data from some of these samples have been reported elsewhere (23).

Statistical Analyses. Fisher's exact tests were used to assess the relation between HER2 mutations and each factor. All statistical tests were two-sided and P < 0.05 were considered statistically significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Preliminary sequencing of the entire HER2 TK domain (exons 18-24) in 96 unselected NSCLC samples or sequencing of the first four exons of the TK domain (exons 18-21) in which EGFR mutations are limited, in 200 unselected NSCLC samples, and 28 breast carcinoma samples indicated that mutations were limited to exon 20. Because one missense mutation in exon 19 was reported previously in a NSCLC tumor (22), further analyses were limited to these two exons.

Mutations were limited to NSCLC and were absent in 36 neuroendocrine lung tumors (SCLC, large cell neuroendocrine carcinoma, and bronchial carcinoids) and tumors from other sites. A total of 11 (1.6%) mutations were detected in 671 primary NSCLC cases and one (1.3%) mutation was found in 80 NSCLC cell lines (Table 1). All mutations were in-frame duplications/insertions. Corresponding nonmalignant tissues was available from 9 of 11 mutant cases, and the HER2 mutations were confirmed as being somatic in origin. No missense mutations were found. According to the electropherograms (Fig. 1), most mutations were heterozygous, whereas NCI-H1781 (Fig. 1B) and Japan 79 (Fig. 1D) seemed to be homozygous (no wild sequence was detected). These results indicated that allelic imbalance due to the loss of wild allele or selective amplification of the mutant allele occurred in these samples.



View larger version (42K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Electropherograms demonstrating mutational patterns. A, wild-type sequence in nonmalignant lung tissue. B, 3-bp insertion (D27: homozygous) in NCI-H1781. C, 3-bp insertion (D22: heterozygous) in primary tumor. D, 12-bp duplication/insertion (D21: homozygous) in primary tumor.

 
All 11 HER2 mutant cases had adenocarcinoma histology and seven cases occurred in female patients (Table 2). Of the 11 mutant cases, nine of the subjects were never smokers or very light smoker (0.5 pack year history). By contrast, 420 (64%) of the 660 subjects whose tumors lacked mutations were smokers. HER2 mutations preferentially targeted Oriental countries (Japan and Taiwan; 2.4%) compared with Western countries (the United States and Australia; 0.3%) and female gender (2.7%) compared with male gender (1.0%); however, these differences were not statistically significant (P = 0.06 and 0.12 respectively). They occurred frequently in never smoker (3.2%) than in smoker (0.7%) and in adenocarcinoma (2.8%) than other histologies (0%; P = 0.02 and 0.004, respectively; Table 1). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). These findings are similar to the subpopulations of lung cancers in whom EGFR mutations occur as previously shown by us and others (7, 23). In the selected subgroup of Oriental female never smokers with adenocarcinoma histology, the frequency of EGFR mutations was 61% and of HER2 mutations was 4.3%. These results suggest that similar genetic factors and possibly carcinogen(s) or other environmental factor(s) affect the occurrence of mutations in both genes.


View this table:
[in this window]
[in a new window]

  		Table 2. HER2 mutation in lung cancer

 
All of the HER2 mutations were in-frame duplications/insertions in a small stretch of exon 20 (Fig. 2; Table 2). Whereas they were of four different types, a 12-bp duplication/ insertion coding for the amino acids YVMA at codon 776 was the major pattern (6 of 11 mutations). We also detected a 9-bp duplication/insertion (2 of 11 mutations) and three individual base pair de novo insertions. Interestingly, HER2 mutations target the identical corresponding nine-codon region in exon 20 as did EGFR duplications/insertions (Fig. 2). EGFR mutations target important structures around the ATP binding cleft which is also the docking site of the TK inhibitors (9, 23), including the phosphate binding loop, the {alpha}C-helix, and the activation loop. In-frame duplications/insertions of EGFR occur at the COOH-terminal end of {alpha}C-helix, and postulated by us (9) presumably result in configurational changes causing a shift of the helical axis, narrowing the ATP binding cleft and resulting in both increased gene activation and TK inhibitor sensitivity.



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Amino acid alignments of the tyrosine kinase domain in EGFR and HER2. {blacktriangleup} and {blacktriangledown}, duplications/insertions in this study (for HER2) or previously reported by us for EGFR (23). {triangleup}, HER2 duplications/insertions described by Stephens et al. (22). *, nonconserved amino acid.

 
It is of interest to compare our findings with those previously reported (22). Stephens et al. found two types of duplications/insertions in exon 20 (total of four cases). Whereas these were different from the ones we found (Fig. 2), all duplications/insertions from both studies targeted the same eight-codon region (codons 774-781). All of the mutations they identified in lung cancers were in adenocarcinomas (similar to our findings). However, four of the five mutations in their cases were in current or former smokers, in contrast to our findings that the mutations targeted never smokers. Of interest, in their series, EGFR mutations in lung adenocarcinomas were less frequent than HER2 mutations (although we are not informed as to which exons were examined). However, Stephens et al. do not present any detailed data regarding gender, histology, ethnicity, smoking status, or even the geographic location of their lung cancers. Thus, a detailed comparison with our findings is not possible.

We previously reported that EGFR and KRAS mutations do not occur simultaneously (23). Ras/Raf/mitogen-activated protein kinase signaling is one of the important EGFR downstream pathways. The additional cases analyzed in the present study confirm and extend our previous findings. KRAS mutations were detected in 54 (8%) and EGFR mutations were detected in 149 (22%) of 671 NSCLC patients (Table 1). In 80 NSCLC cell lines, KRAS mutations were detected in 20 (25%) and EGFR mutations were detected in eight (10%; 3). Mutations in more than one of these genes were never found simultaneously in the same tumor, suggesting that activation of either EGFR, HER2, or oncogenic KRAS is sufficient for lung carcinogenesis. Of interest, HER2 is the preferential heterodimer partner for EGFR, and interactions between family members may play a role in lung cancer pathogenesis. Previously, we hypothesized that at least two distinct molecular pathways are involved in the pathogenesis of lung adenocarcinomas, one involving EGFR mutations in never smokers and the other involving oncogenic KRAS mutations in smokers (9). HER2 mutations may contribute to lung adenocarcinoma pathogenesis in never smokers. However, only 51% of adenocarcinomas in the present study had mutations in any one of the three genes, indicating a role for other as yet unknown genetic or epigenetic changes. Of interest, in the highly selected subgroup of Oriental female never smokers with adenocarcinoma histology lacking EGFR mutations, the frequency of HER2 mutations was 11%


View this table:
[in this window]
[in a new window]

  		Table 3. EGFR, HER2, and KRAS mutation status in NSCLC cell lines

 
Oncogenic mutations activate kinases by disrupting the autoinhibitory mechanisms that normally stabilize their inactive forms (1). They target structures around the ATP binding cleft that are involved in phosphorylation events. These structures include the phosphate binding and activation loops. Of interest, very different kinases, such as the receptor tyrosine kinase PDGFR family and the intracellular serine/threonine kinase BRAF share similar oncogenic hotspots (1). Deletions and duplications/insertions on either side of the {alpha}C-helix are also characteristic of EGFR mutations, and we have postulated that such mutations alter the angle of the ATP binding cleft, resulting in greater activity (9). Of interest, with one exception, all of the HER2 mutations in lung cancers described by us and by Stephens et al. (22) have been in-frame duplications/insertions targeting a region of eight codons in exon 20 on the COOH-terminal side of the {alpha}C-helix. With one exception they occur adjacent to or replaced nonconserved residues (Fig. 2). Whereas the activating function of these specific mutations has not been clarified, the remarkable similarities between the mutations in EGFR and HER2 suggest that they are functional. However, the function of the very rare, often unique, point mutations found in NSCLC and other cancers is less certain.

In summary, we found a relatively modest frequency of somatic HER2 gene mutations limited to the adenocarcinoma subtype of lung cancer. The mutations targeted never or light smokers, Oriental ethnicity and female gender. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented in molecular medicine. These finding suggest the necessity of epidemiologic studies focused on finding a common underlying etiology. HER2 mutant cell line NCI-H1781 is resistant in vitro to gefitinib (26), which preferentially inhibits the TK activity of EGFR. The identification of NCI-H1781 with its HER2 mutation provides an important new resource for preclinical therapeutic studies looking a HER2 targeted agents. However, broad spectrum TK inhibitors may also offer the advantage of simultaneously targeting multiple members of the EGFR family thereby interfering with the cooperation that exists between receptors (27).


   Acknowledgments
 
Grant support: Specialized Program of Research Excellence in Lung Cancer grant P50CA70907 and Early Detection Research Network, National Cancer Institute grant 5U01CA8497102 (Bethesda, MD).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/29/04. Revised 12/17/04. Accepted 12/23/04.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Dibb NJ, Dilworth SM, Mol CD. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer 2004;4:718–27.[CrossRef][Medline]
  2. Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. Science 2004;303:1800–5.[Abstract/Free Full Text]
  3. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7.[Abstract/Free Full Text]
  4. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80.[Abstract/Free Full Text]
  5. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.[Abstract/Free Full Text]
  6. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.[Abstract/Free Full Text]
  7. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306–11.[Abstract/Free Full Text]
  8. Weinstein IB. Cancer. Addiction to oncogenes: the Achilles heal of cancer. Science 2002;297:63–4.[Free Full Text]
  9. Gazdar AF, Shigematsu H, Herz J, Minna JD. Mutations and addiction to EGFR: the Achilles "heal" of lung cancers? Trends Mol Med 2004;10:481–6.[CrossRef][Medline]
  10. Citri A, Skaria KB, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 2003;284:54–65.[CrossRef][Medline]
  11. Normanno N, Bianco C, De Luca A, Maiello MR, Salomon DS. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 2003;10:1–21.[Abstract]
  12. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.[Abstract/Free Full Text]
  13. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–12.[Abstract/Free Full Text]
  14. Bunn PA Jr, Helfrich B, Soriano AF, et al. Expression of Her-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. Clin Cancer Res 2001;7:3239–50.[Abstract/Free Full Text]
  15. Cappuzzo F, Gregorc V, Rossi E, et al. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 2003;21:2658–63.[Abstract/Free Full Text]
  16. Heinmoller P, Gross C, Beyser K, et al. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin Cancer Res 2003;9:5238–43.[Abstract/Free Full Text]
  17. Hirsch FR, Varella-Garcia M, Franklin WA, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 2002;86:1449–56.[CrossRef][Medline]
  18. Slamon DJ, Leyland-Jones B, Shak S, 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.[Abstract/Free Full Text]
  19. Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 2004;22:1180–7.[Abstract/Free Full Text]
  20. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 2004;15:19–27.[Abstract/Free Full Text]
  21. Zinner RG, Glisson BS, Fossella FV, et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer 2004;44:99–110.[CrossRef][Medline]
  22. Stephens P, Hunter C, Bignell G, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525–6.[Medline]
  23. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. In press 2005.
  24. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710–7.[Abstract/Free Full Text]
  25. Phelps RM, Johnson BE, Ihde DC, et al. NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem Suppl 1996;24:32–91.[Medline]
  26. Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 2004;64:7241–4.[Abstract/Free Full Text]
  27. Britten CD. Targeting ErbB receptor signaling: a pan-ErbB approach to cancer. Mol Cancer Ther 2004;3:1335–42.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
C. M. Rudin, E. Avila-Tang, C. C. Harris, J. G. Herman, F. R. Hirsch, W. Pao, A. G. Schwartz, K. H. Vahakangas, and J. M. Samet
Lung Cancer in Never Smokers: Molecular Profiles and Therapeutic Implications
Clin. Cancer Res., September 15, 2009; 15(18): 5646 - 5661.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
K. Pedersen, P.-D. Angelini, S. Laos, A. Bach-Faig, M. P. Cunningham, C. Ferrer-Ramon, A. Luque-Garcia, J. Garcia-Castillo, J. L. Parra-Palau, M. Scaltriti, et al.
A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis
Mol. Cell. Biol., June 15, 2009; 29(12): 3319 - 3331.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. Brambilla and A. Gazdar
Pathogenesis of lung cancer signalling pathways: roadmap for therapies
Eur. Respir. J., June 1, 2009; 33(6): 1485 - 1497.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. A. Perera, D. Li, T. Shimamura, M. G. Raso, H. Ji, L. Chen, C. L. Borgman, S. Zaghlul, K. A. Brandstetter, S. Kubo, et al.
HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy
PNAS, January 13, 2009; 106(2): 474 - 479.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
M. S. Anglesio, J. M. Arnold, J. George, A. V. Tinker, R. Tothill, N. Waddell, L. Simms, B. Locandro, S. Fereday, N. Traficante, et al.
Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors
Mol. Cancer Res., November 1, 2008; 6(11): 1678 - 1690.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
R. S. Herbst and A. Sandler
Bevacizumab and Erlotinib: A Promising New Approach to the Treatment of Advanced NSCLC
Oncologist, November 1, 2008; 13(11): 1166 - 1176.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Radiol.Home page
C M West, L Joseph, and S Bhana
Epidermal growth factor receptor-targeted therapy
Br. J. Radiol., October 1, 2008; 81(Special_Issue_1): S36 - S44.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
R. S. Herbst, J. V. Heymach, and S. M. Lippman
Lung Cancer
N. Engl. J. Med., September 25, 2008; 359(13): 1367 - 1380.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Shivapurkar, V. Stastny, N. Okumura, L. Girard, Y. Xie, C. Prinsen, F. B. Thunnissen, I. I. Wistuba, B. Czerniak, E. Frenkel, et al.
Cytoglobin, the Newest Member of the Globin Family, Functions as a Tumor Suppressor Gene
Cancer Res., September 15, 2008; 68(18): 7448 - 7456.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Yamamoto, H. Shigematsu, M. Nomura, W. W. Lockwood, M. Sato, N. Okumura, J. Soh, M. Suzuki, I. I. Wistuba, K. M. Fong, et al.
PIK3CA Mutations and Copy Number Gains in Human Lung Cancers
Cancer Res., September 1, 2008; 68(17): 6913 - 6921.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, et al.
Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor
Mol. Cancer Ther., July 1, 2008; 7(7): 1880 - 1889.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M.-J. Ahn, B.-B. Park, J. S. Ahn, S. W. Kim, H.-T. Kim, J. S. Lee, J. H. Kang, J. Y. Cho, H. S. Song, S. H. Park, et al.
Are There Any Ethnic Differences in Molecular Predictors of Erlotinib Efficacy in Advanced Non-Small Cell Lung Cancer?
Clin. Cancer Res., June 15, 2008; 14(12): 3860 - 3866.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Trowe, S. Boukouvala, K. Calkins, R. E. Cutler Jr., R. Fong, R. Funke, S. B. Gendreau, Y. D. Kim, N. Miller, J. R. Woolfrey, et al.
EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation
Clin. Cancer Res., April 15, 2008; 14(8): 2465 - 2475.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
N. Shivapurkar, V. Stastny, Y. Xie, C. Prinsen, E. Frenkel, B. Czerniak, F. B. Thunnissen, J. D. Minna, and A. F. Gazdar
Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay
Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 995 - 1000.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al.
Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib
Cancer Res., January 15, 2008; 68(2): 571 - 579.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M.-E. Legrier, C.-P. H. Yang, H.-G. Yan, L. Lopez-Barcons, S. M. Keller, R. Perez-Soler, S. B. Horwitz, and H. M. McDaid
Targeting Protein Translation in Human Non Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression
Cancer Res., December 1, 2007; 67(23): 11300 - 11308.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
S Beauclair, P Formento, J. Fischel, W Lescaut, R Largillier, E Chamorey, P Hofman, J. Ferrero, G Pages, and G Milano
Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity
Ann. Onc., August 1, 2007; 18(8): 1335 - 1341.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. P. Piechocki, G. H. Yoo, S. K. Dibbley, and F. Lonardo
Breast Cancer Expressing the Activated HER2/neu Is Sensitive to Gefitinib In vitro and In vivo and Acquires Resistance through a Novel Point Mutation in the HER2/neu
Cancer Res., July 15, 2007; 67(14): 6825 - 6843.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Mounawar, A. Mukeria, F. Le Calvez, R. J. Hung, H. Renard, A. Cortot, C. Bollart, D. Zaridze, P. Brennan, P. Boffetta, et al.
Patterns of EGFR, HER2, TP53, and KRAS Mutations of p14arf Expression in Non-Small Cell Lung Cancers in Relation to Smoking History
Cancer Res., June 15, 2007; 67(12): 5667 - 5672.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
F. Cappuzzo, C. Ligorio, P. A. Janne, L. Toschi, E. Rossi, R. Trisolini, D. Paioli, A. J. Holmes, E. Magrini, G. Finocchiaro, et al.
Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization-Positive/Phospho-Akt-Positive or Never Smoker Patients With Advanced Non-Small-Cell Lung Cancer: The ONCOBELL Trial
J. Clin. Oncol., June 1, 2007; 25(16): 2248 - 2255.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W. Xu and L. Neckers
Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells
Clin. Cancer Res., March 15, 2007; 13(6): 1625 - 1629.
[Full Text] [PDF]

Home page
 JCOHome page
A. F. Gazdar and M. J. Thun
Lung Cancer, Smoke Exposure, and Sex
J. Clin. Oncol., February 10, 2007; 25(5): 469 - 471.
[Full Text] [PDF]

Home page
 The OncologistHome page
L. Toschi and F. Cappuzzo
Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Oncologist, February 1, 2007; 12(2): 211 - 220.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
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]

Home page
 Cancer Res.Home page
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]

Home page
 Clin. Cancer Res.Home page
C. Swanton, A. Futreal, and T. Eisen
Her2-targeted therapies in non-small cell lung cancer.
Clin. Cancer Res., July 15, 2006; 12(14): 4377s - 4383s.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. H. Johnson
Targeted therapies in combination with chemotherapy in non-small cell lung cancer.
Clin. Cancer Res., July 15, 2006; 12(14): 4451s - 4457s.
[Abstract] [Full Text] [PDF]

Home page
 J. Mol. Diagn.Home page
M. Sonobe, T. Manabe, H. Wada, and F. Tanaka
Lung Adenocarcinoma Harboring Mutations in the ERBB2 Kinase Domain
J. Mol. Diagn., July 1, 2006; 8(3): 351 - 356.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. Shimamura, H. Ji, Y. Minami, R. K. Thomas, A. M. Lowell, K. Shah, H. Greulich, K. A. Glatt, M. Meyerson, G. I. Shapiro, et al.
Non-Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2 G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth Factor Receptor and ERBB2 Inhibitor HKI-272.
Cancer Res., July 1, 2006; 66(13): 6487 - 6491.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
F. Cappuzzo, L. Bemis, and M. Varella-Garcia
HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.
N. Engl. J. Med., June 15, 2006; 354(24): 2619 - 2621.
[Full Text] [PDF]

Home page
 Eur Respir JHome page
E. Brambilla and S. Lantuejoul
Telomerase activation in adenocarcinoma-bronchioloalveolar carcinoma.
Eur. Respir. J., June 1, 2006; 27(6): 1079 - 1081.
[Full Text] [PDF]

Home page
 The OncologistHome page
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]

Home page
 J. Biol. Chem.Home page
A. Citri, D. Harari, G. Shohat, P. Ramakrishnan, J. Gan, S. Lavi, M. Eisenstein, A. Kimchi, D. Wallach, S. Pietrokovski, et al.
Hsp90 Recognizes a Common Surface on Client Kinases
J. Biol. Chem., May 19, 2006; 281(20): 14361 - 14369.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
E. Calvo and J. Baselga
Ethnic Differences in Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
J. Clin. Oncol., May 10, 2006; 24(14): 2158 - 2163.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S.-W. Han, T.-Y. Kim, Y. K. Jeon, P. G. Hwang, S.-A. Im, K.-H. Lee, J. H. Kim, D.-W. Kim, D. S. Heo, N. K. Kim, et al.
Optimization of Patient Selection for Gefitinib in Non-Small Cell Lung Cancer by Combined Analysis of Epidermal Growth Factor Receptor Mutation, K-ras Mutation, and Akt Phosphorylation
Clin. Cancer Res., April 15, 2006; 12(8): 2538 - 2544.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
I. Y. S. Tam, L. P. Chung, W. S. Suen, E. Wang, M. C.M. Wong, K. K. Ho, W. K. Lam, S. W. Chiu, L. Girard, J. D. Minna, et al.
Distinct Epidermal Growth Factor Receptor and KRAS Mutation Patterns in Non-Small Cell Lung Cancer Patients with Different Tobacco Exposure and Clinicopathologic Features
Clin. Cancer Res., March 1, 2006; 12(5): 1647 - 1653.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. S. Rao, N. Kremenevskaja, R. von Wasielewski, V. Jakubcakova, S. Kant, J. Resch, and G. Brabant
Wnt/{beta}-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer
J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 159 - 168.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. W. Lee, Y. H. Soung, S. H. Seo, S. Y. Kim, C. H. Park, Y. P. Wang, K. Park, S. W. Nam, W. S. Park, S. H. Kim, et al.
Somatic Mutations of ERBB2 Kinase Domain in Gastric, Colorectal, and Breast Carcinomas
Clin. Cancer Res., January 1, 2006; 12(1): 57 - 61.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. L. Yauch, T. Januario, D. A. Eberhard, G. Cavet, W. Zhu, L. Fu, T. Q. Pham, R. Soriano, J. Stinson, S. Seshagiri, et al.
Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients
Clin. Cancer Res., December 15, 2005; 11(24): 8686 - 8698.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
O. C. Ioachimescu and A. C. Mehta
From cystic pulmonary airway malformation, to bronchioloalveolar carcinoma and adenocarcinoma of the lung
Eur. Respir. J., December 1, 2005; 26(6): 1181 - 1187.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
E. E.W. Cohen, M. W. Lingen, L. E. Martin, P. L. Harris, B. W. Brannigan, S. M. Haserlat, R. A. Okimoto, D. C. Sgroi, S. Dahiya, B. Muir, 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., November 15, 2005; 11(22): 8105 - 8108.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
T. Takano, Y. Ohe, H. Sakamoto, K. Tsuta, Y. Matsuno, U. Tateishi, S. Yamamoto, H. Nokihara, N. Yamamoto, I. Sekine, et al.
Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non-Small-Cell Lung Cancer
J. Clin. Oncol., October 1, 2005; 23(28): 6829 - 6837.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Davies, C. Hunter, R. Smith, P. Stephens, C. Greenman, G. Bignell, J. Teague, A. Butler, S. Edkins, C. Stevens, et al.
Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer
Cancer Res., September 1, 2005; 65(17): 7591 - 7595.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Shibata, S. Uryu, A. Kokubu, F. Hosoda, M. Ohki, T. Sakiyama, Y. Matsuno, R. Tsuchiya, Y. Kanai, T. Kondo, et al.
Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features
Clin. Cancer Res., September 1, 2005; 11(17): 6177 - 6185.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
F. Cappuzzo, M. Varella-Garcia, H. Shigematsu, I. Domenichini, S. Bartolini, G. L. Ceresoli, E. Rossi, V. Ludovini, V. Gregorc, L. Toschi, et al.
Increased HER2 Gene Copy Number Is Associated With Response to Gefitinib Therapy in Epidermal Growth Factor Receptor-Positive Non-Small-Cell Lung Cancer Patients
J. Clin. Oncol., August 1, 2005; 23(22): 5007 - 5018.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
R. J. Gilbertson
ERBB2 in Pediatric Cancer: Innocent Until Proven Guilty
Oncologist, August 1, 2005; 10(7): 508 - 517.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
F. J. Kaye
A Curious Link Between Epidermal Growth Factor Receptor Amplification and Survival: Effect of "Allele Dilution" on Gefitinib Sensitivity?
J Natl Cancer Inst, May 4, 2005; 97(9): 621 - 623.
[Full Text] [PDF]

Home page
 Cold Spring Harb Symp Quant BiolHome page
H. VARMUS, W. PAO, K. POLITI, K. PODSYPANINA, and Y.-C.N. DU
Oncogenes Come of Age
Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 1 - 9.
[Abstract] [PDF]

Home page
 Cold Spring Harb Symp Quant BiolHome page
P.A. FUTREAL, R. WOOSTER, and M.R. STRATTON
Somatic Mutations in Human Cancer: Insights from Resequencing the Protein Kinase Gene Family
Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 43 - 49.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shigematsu, H.
Right arrow Articles by Gazdar, A. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shigematsu, H.
Right arrow Articles by Gazdar, A. F.

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 Meeting Abstracts Online