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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
J. Guillermo Paez,1,2*
Pasi A. Jänne,1,2*
Jeffrey C. Lee,1,3*
Sean Tracy,1
Heidi Greulich,1,2
Stacey Gabriel,4
Paula Herman,1
Frederic J. Kaye,5
Neal Lindeman,6
Titus J. Boggon,1,3
Katsuhiko Naoki,1
Hidefumi Sasaki,7
Yoshitaka Fujii,7
Michael J. Eck,1,3
William R. Sellers,1,2,4
Bruce E. Johnson,1,2
Matthew Meyerson1,3,4
Abstract:
Receptor tyrosine kinase genes were sequenced in non–smallcell lung cancer (NSCLC) and matched normal tissue. Somaticmutations of the epidermal growth factor receptor gene EGFRwere found in 15of 58 unselected tumors from Japan and 1 of61 from the United States. Treatment with the EGFR kinase inhibitorgefitinib (Iressa) causes tumor regression in some patientswith NSCLC, more frequently in Japan. EGFR mutations were foundin additional lung cancer samples from U.S. patients who respondedto gefitinib therapy and in a lung adenocarcinoma cell linethat was hypersensitive to growth inhibition by gefitinib, butnot in gefitinib-insensitive tumors or cell lines. These resultssuggest that EGFR mutations may predict sensitivity to gefitinib.
1 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. 3 Departments of Pathology and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. 4 The Broad Institute at MIT and Harvard, Cambridge, MA 02142, USA. 5 Genetics Branch, National Cancer Institute, National Naval Medical Center, Bethesda, MD 20889, USA. 6 Department of Pathology, Brigham and Women's Hospital, Boston MA 02115, USA. 7 Department of Surgery 2, Nagoya City University Medical School, Nagoya 467-8601, Japan.
Note added in proof: Similar results are being reported by T.J. Lynch et al. (28).
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: William_Sellers{at}dfci.harvard.edu; Bruce_Johnson{at}dfci.harvard.edu; Matthew_Meyerson{at}dfci.harvard.edu
Protein kinase activation by somatic mutation or chromosomalalteration is a common mechanism of tumorigenesis (1). Inhibitionof activated protein kinases through the use of targeted smallmolecule drugs or antibody-based strategies has emerged as aneffective approach to cancer therapy (2–4). Recently,systematic analysis of kinase genes has identified mutationsof the protein serine-threonine kinase gene BRAF in melanomaand other human cancers (5) and of multiple tyrosine kinasegenes and the phosphatidylinositol 3-kinase p110 catalytic subunitgene PIK3CA in human colorectal carcinoma (6, 7).
Lung carcinoma is the leading cause of cancer deaths in theUnited States and worldwide for both men and women (8). Chemotherapyfor non–small cell lung carcinoma (NSCLC), which accountsfor approximately 85% of lung cancer cases, remains marginallyeffective (9).
Recently, the epidermal growth factor receptor (EGFR) tyrosinekinase inhibitor, gefitinib (Iressa), was approved in Japanand the United States for the treatment of NSCLC. The originalrationale for its use was the observation that EGFR is moreabundantly expressed in lung carcinoma tissue than in adjacentnormal lung (10). However, EGFR expression as detected by immunohistochemistryis not an effective predictor of response to gefitinib (11).
Clinical trials have revealed significant variability in theresponse to gefitinib, with higher responses seen in Japanesepatients than in a predominantly European-derived population(27.5% versus 10.4%, in a multi-institutional phase II trial)(12). In the United States, partial clinical responses to gefitinibhave been observed most frequently in women, in nonsmokers,and in patients with adenocarcinomas (13–15).
To determine whether mutation of receptor tyrosine kinases playsa causal role in NSCLC, we searched for somatic genetic alterationsin a set of 119 primary NSCLC tumors, consisting of 58 samplesfrom Nagoya City University Hospital in Japan and 61 from theBrigham and Women's Hospital in Boston, Massachusetts. The tumorsincluded 70 lung adenocarcinomas and 49 other NSCLC tumors from74 male and 45 female patients, none of whom had documentedtreatment with gefitinib.
As an initial screen, we amplified and sequenced the exons encodingthe activation loops of 47 of the 58 human receptor tyrosinekinase genes (16) (table S1) from genomic DNA from a subsetof 58 NSCLC samples that included 41 lung adenocarcinomas. Threeof the tumors, all lung adenocarcinomas, showed heterozygousmissense mutations in EGFR not present in the DNA from normallung tissue from the same patients (table S2; S0361, S0388,S0389). No mutations were detected in amplicons from other receptortyrosine kinase genes. All three tumors had the same EGFR mutation,predicted to change leucine-858 to arginine (Fig. 1A; CTG CGG;L858R).
Fig. 1.. Sequence alignment of selected regions within the EGFR and B-Raf kinase domains. Depiction of each type of EGFR mutation in human NSCLC. EGFR (gb:X00588) mutations in NSCLC tumors are highlighted in yellow. B-Raf (gb:M95712) mutations in multiple tumor types (5) are highlighted in blue. Asterisks denote residues conserved between EGFR and B-Raf. (A) L858R mutations in activation loop. (B) G719S mutant in P-loop. (C) Deletion mutants in EGFR exon 19.
[View Larger Version of this Image (37K GIF file)]
We next examined exons 2 through 25 of EGFR in the completecollection of 119 NSCLC tumors. Exon sequencing of genomic DNArevealed missense and deletion mutations of EGFR in a totalof 16 tumors, all within exons 18 through 21 of the kinase domain.All sequence alterations in this group were heterozygous inthe tumor DNA; in each case, paired normal lung tissue fromthe same patient showed wild-type sequence, confirming thatthe mutations are somatic in origin. The distribution of nucleotideand protein sequence alterations, and the patient characteristicsassociated with these abnormalities, are summarized in tableS2.
Substitution mutations G719S and L858R were detected in twoand three tumors, respectively. These mutations are locatedin the GXGXXG motif of the nucleotide triphosphate binding domainor P-loop and adjacent to the highly conserved DFG motif inthe activation loop (17), respectively. The mutated residuesare nearly invariant in all protein kinases, and the analogousresidues (G463 and L596) in the B-Raf protein serine-threoninekinase are somatically mutated in colorectal, ovarian, and lungcarcinomas (5, 18) (Fig. 1, A and B).
We also detected multiple deletion mutations clustered in theregion spanning codons 746 to 759 within the kinase domain ofEGFR. Ten tumors carried one of two overlapping 15-nucleotidedeletions eliminating EGFR codons 746 to 750, starting at nucleotide2235 or 2236 (Del-1) (Fig. 1C and table S2). EGFR DNA from anothertumor displayed a heterozygous 24-nucleotide gap leading tothe deletion of codons 752 to 759 (Del-2) (Fig. 1C). Representativechromatograms are shown in fig. S1.
The positions of the substitution mutations and the Del-1 deletionin the three-dimensional structure of the active form of theEGFR kinase domain (19) are shown in Fig. 2. Note that the sequencealterations cluster around the active site of the kinase andthat the substitution mutations lie in the activation loop andglycine-rich P-loop, structural elements known to be importantfor autoregulation in many protein kinases (17).
Fig. 2.. Positions of missense mutations G719S and L858R and the Del-1 deletion in the three-dimensional structure of the EGFR kinase domain. The activation loop is shown in yellow, the P-loop is in blue, and the C-lobe and N-lobe are as indicated. The residues targeted by mutation or deletion are highlighted in red. The Del-1 mutation targets the residues ELREA in codons 746 to 750.
[View Larger Version of this Image (51K GIF file)]
The EGFR mutations show a striking correlation with patientcharacteristics. Mutations were more frequent in adenocarcinomas(15/70 or 21%) than in other NSCLCs (1/49 or 2%), more frequentin women (9/45 or 20%) than in men (7/74 or 9%), and more frequentin the patients from Japan (15/58 or 26%, and 14/41 adenocarcinomasor 32%) than in those from the United States (1/61 or 2%, and1/29 adenocarcinomas or 3%). The highest fraction of EGFR mutationswas observed in Japanese women with adenocarcinoma (8/14 or57%). Notably, the patient characteristics that correlate withthe presence of EGFR mutations are those that correlate withclinical response to gefitinib treatment.
To investigate whether EGFR mutations might be a determinantof gefitinib sensitivity, pretreatment NSCLC samples were obtainedfrom 5 patients who responded and 4 patients who progressedduring treatment with gefitinib out of more than 125 patientstreated at the Dana-Farber Cancer Institute either on an expandedaccess program or after regulatory approval of gefitinib (13).Four of the patients had partial radiographic responses (50%tumor regression in a computed tomography scan after 2 monthsof treatment), whereas the fifth patient experienced dramaticsymptomatic improvement in less than 2 months. All of the patientswere from the United States and were Caucasian.
While sequencing of the kinase domain (exons 18 through 24)revealed no mutations in tumors from the four patients who progressedon gefitinib, all five tumors from gefitinib-responsive patientsharbored EGFR kinase domain mutations. The chi-square test revealedthe difference in EGFR mutation frequency between gefitinibresponders (5/5) and nonresponders (0/4) to be statisticallysignificant with P = 0.0027, whereas the difference betweenthe gefitinib responders and unselected U.S. NSCLC patients(5/5 versus 1/61) was also significant with P < 10–12(20). The EGFR L858R mutation, previously observed in the unselectedtumors, was identified in one gefitinib-sensitive lung adenocarcinoma(Fig. 1A and table S3, IR3T). Three gefitinib-sensitive tumorscontained heterozygous in-frame deletions (Fig. 1C and tableS3, Del-3 in two cases and Del-4 in one), and one containeda homozygous inframe deletion (Fig. 1C and table S3, Del-5).Each of these deletions was found within codons 746 to 753 ofEGFR, where deletions were also found in unselected tumors.Each of these three deletions is also associated with an aminoacid substitution (table S3). In all four samples where matchednormal tissue was available, these mutations were confirmedas somatic.
To determine whether mutations in EGFR confer gefitinib sensitivityin vitro, the mutation status and response to gefitinib weredetermined in four lung adenocarcinoma and bronchioloalveolarcarcinoma cell lines. The H3255 cell line was originally derivedfrom a malignant pleural effusion from a Caucasian female nonsmokerwith lung adenocarcinoma (21). This cell line was 50 times assensitive to gefitinib as the other lines, with an IC50 of 40nM for cell survival in a 72-hour assay (Fig. 3A).
Fig. 3.. A lung adenocarcinoma cell line with EGFR receptor mutation is sensitive to growth and signaling inhibition by gefitinib. (A) Cells were treated with gefitinib at the indicated concentrations, and viable cells were measured after 72 hours of treatment. Percentage of cell growth is shown relative to untreated controls. H3255 cells have the EGFR L858R mutation, whereas the three remaining cell lines have wild-type EGFR (WT). (B) Inhibition of EGFR phosphorylation and of downstream phosphorylation of Akt and Erk1/2. The cell lines were treated with gefitinib for 24 hours. Cell extracts were immunoblotted to detect the indicated protein species. Akt, v-akt murine thymoma viral oncogene homolog; Erk, extracellular signal-responsive kinase.
[View Larger Version of this Image (27K GIF file)]
Treatment with 100 nM gefitinib completely inhibited EGFR autophosphorylationin H3255 (Fig. 3B). Such treatment also inhibited the phosphorylationof known down-stream targets of EGFR such as the extracellularsignal-regulated kinase 1/2 (ERK1/2) and the v-akt murine thymomaviral oncogene homolog (AKT kinase) (Fig. 3B), a correlationthat has been noted by others (22). In contrast, the other threecell lines showed comparable levels of inhibition of targetprotein phosphorylation only when gefitinib was present at concentrationsroughly 100 times as high (Fig. 3B).
The sequence analysis of EGFR cDNA in these four cell linesshowed the L858R mutations in H3255 (table S3), whereas theother three cell lines did not contain EGFR mutations. We alsoconfirmed the presence of the L858R mutation in the primarytumor from which H3255 was derived (table S3, IRG), althoughno matched normal tissue was available. The results suggestthat L858R mutant EGFR is particularly sensitive to inhibitionby gefitinib compared with the wild-type enzyme and that thislikely accounts for the extraordinary drug sensitivity of theH3255 cell line.
The identification of EGFR mutations in a subset of human lungcarcinomas and the association between EGFR mutation and gefitinibsensitivity extend the emerging paradigm whereby genetic alterationsin specific kinases, and not simply kinase expression, rendertumors sensitive to selective inhibitors as is the case forimatinib treatment of c-kit mutant gastrointestinal stromaltumors (23). Thus, although randomized trials of cytotoxic therapywith or without gefitinib revealed no survival benefit for thegefitinib-treated NSCLC patients (24, 25), our current datasuggest that gefitinib may be particularly effective for treatinglung cancers with somatic EGFR mutations and that prospectiveclinical trials of EGFR inhibition in patients with EGFR mutationsmight reveal increased patient survival. Identification of EGFRmutations in other malignancies, perhaps including glioblastomasin which EGFR alterations are already known (26), may identifyother patients who could similarly benefit from treatment withEGFR inhibitors.
Important questions remain to be answered, including whetherthese alterations result in activated and transforming allelesof EGFR, whether receptors harboring such mutations will showdifferential sensitivity to any of the multiple EGFR small moleculeinhibitors, and whether EGFR receptors harboring such mutationsare inhibited by antibodies directed against the extracellulardomain. Furthermore, it will be of interest to determine whetherresistance to EGFR inhibition emerges through secondary mutationas is the case in imatinib-treated chronic myelogenous leukemia(27). These results should stimulate further in vitro studiesregarding these questions.
Finally, the striking differences in the frequency of EGFR mutationand response to gefitinib between Japanese and U.S. patientsraise general questions regarding variations in the molecularpathogenesis of cancer in different ethnic, cultural, and geographicgroups and argue for the benefit of population diversity incancer clinical trials.
18"> K. Naoki, T. H. Chen, W. G. Richards, D. J. Sugarbaker, M. Meyerson, Cancer Res.62, 7001 (2002).[Abstract/Free Full Text]
19"> J. Stamos, M. X. Sliwkowski, C. Eigenbrot, J. Biol. Chem.277, 46265 (2002).[Abstract/Free Full Text]
20"> Note that the frequency of EGFR mutation in the unselected U.S. patients, 1 of 61, appears to be low when compared with the frequency of reported gefitinib response at 10.4%. This difference has a modest statistical significance (P = 0.025 by the chi-square test). Thus, this result could still be due to chance, to a fraction of responders who do not have EGFR mutations, or to failure to detect EGFR mutations experimentally in this tumor collection. If the frequency of EGFR mutation in gefitinib-responsive U.S. patients (5/5) is compared with the expected frequency of gefitinib response (10.4%), the chisquare probability is again less than 10–12.
We thank D. Altshuler, T. Golub, P. Kantoff, D. Hill, M. Vidal, E. Lander, and D. Livingston for their advice, encouragement, and extraordinary support, and E. Lander and D. Livingston for their thoughtful comments on the manuscript. Supported by the Novartis Research Foundation, the Claudia Adams Barr Fund and the Charles A. Dana Human Cancer Genetics Program of the Dana-Farber Cancer Institute, the Poduska Family Foundation, the Gerhard Andlinger Fund, the Tisch Family Foundation, the Arthur and Linda Gelb Foundation, the Damon-Runyon Cancer Research Foundation, Joan's Legacy, the American Cancer Society, the Flight Attendant Medical Research Institute, the National Cancer Institute Lung Specialized Programs of Research Excellence and K12 programs, and numerous generous donors to the Dana-Farber Cancer Institute. M.J.E., W.R.S., and M.M. receive research funding and consulting fees from Novartis, and B.E.J. receives research funding from Eli Lilly. W.R.S. has served on the advisory board of ImClone Systems Inc. M.M. and W.R.S. have received honoraria for speaking at a meeting sponsored by AstraZeneca Pharmaceuticals. AstraZeneca is the manufacturer of gefitinib.
Received for publication 16 April 2004. Accepted for publication 21 April 2004.
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S. Kondo, S. Iwata, T. Yamada, Y. Inoue, H. Ichihara, Y. Kichikawa, T. Katayose, A. Souta-Kuribara, H. Yamazaki, O. Hosono, et al. (2012)
Clin. Cancer Res.
18, 6326-6338
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Cancer Genes in Lung Cancer: Racial Disparities: Are There Any?.
Predictors of Survival in Never-Smokers with Non-Small Cell Lung Cancer: A Large-Scale, Two-Phase Genetic Study.
X. Pu, Y. Ye, M. R. Spitz, L. Wang, J. Gu, S. M. Lippman, M. A. T. Hildebrandt, W. K. Hong, J. D. Minna, J. A. Roth, et al. (2012)
Clin. Cancer Res.
18, 5983-5991
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Mechanism of Drug Efficacy Within the EGF Receptor Revealed by Microsecond Molecular Dynamics Simulation.
S. Wan, D. W. Wright, and P. V. Coveney (2012)
Mol. Cancer Ther.
11, 2394-2400
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Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology.
S.-H. I. Ou, C. H. Bartlett, M. Mino-Kenudson, J. Cui, and A. J. Iafrate (2012)
Oncologist
17, 1351-1375
|Abstract »|Full Text »|PDF »
A framework for identification of actionable cancer genome dependencies in small cell lung cancer.
M. L. Sos, F. Dietlein, M. Peifer, J. Schottle, H. Balke-Want, C. Muller, M. Koker, A. Richters, S. Heynck, F. Malchers, et al. (2012)
PNAS
109, 17034-17039
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Non-Small Cell Lung Cancer.
D. S. Ettinger, W. Akerley, H. Borghaei, A. C. Chang, R. T. Cheney, L. R. Chirieac, T. A. D'Amico, T. L. Demmy, A. K. P. Ganti, R. Govindan, et al. (2012)
J Natl Compr Canc Netw
10, 1236-1271
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Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors.
D. Ercan, C. Xu, M. Yanagita, C. S. Monast, C. A. Pratilas, J. Montero, M. Butaney, T. Shimamura, L. Sholl, E. V. Ivanova, et al. (2012)
Cancer Discovery
2, 934-947
|Abstract »|Full Text »|PDF »
HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFRT790M Mutation.
K. Takezawa, V. Pirazzoli, M. E. Arcila, C. A. Nebhan, X. Song, E. de Stanchina, K. Ohashi, Y. Y. Janjigian, P. J. Spitzler, M. A. Melnick, et al. (2012)
Cancer Discovery
2, 922-933
|Abstract »|Full Text »|PDF »
Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth.
F. Harbinski, V. J. Craig, S. Sanghavi, D. Jeffery, L. Liu, K. A. Sheppard, S. Wagner, C. Stamm, A. Buness, C. Chatenay-Rivauday, et al. (2012)
Cancer Discovery
2, 948-959
|Abstract »|Full Text »|PDF »
Clinical Outcomes of Thoracic Radiotherapy for Locally Advanced NSCLC with EGFR Mutations or EML4-ALK Rearrangement.
H. HAYASHI, I. OKAMOTO, H. KIMURA, K. SAKAI, Y. NISHIMURA, K. NISHIO, and K. NAKAGAWA (2012)
Anticancer Res
32, 4533-4537
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Lesions in patients with multifocal adenocarcinoma are more frequently in the right upper lobes.
H. Kaneda, Y. Uemura, T. Nakano, Y. Taniguchi, T. Saito, T. Konobu, and Y. Saito (2012)
Interact CardioVasc Thorac Surg
15, 627-632
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Threonine 2609 Phosphorylation of the DNA-Dependent Protein Kinase Is a Critical Prerequisite for Epidermal Growth Factor Receptor-Mediated Radiation Resistance.
P. Javvadi, H. Makino, A. K. Das, Y.-F. Lin, D. J. Chen, B. P. Chen, and C. S. Nirodi (2012)
Mol. Cancer Res.
10, 1359-1368
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Timing of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Patients With Lung Cancer With EGFR Mutations.
T. Moran and L. V. Sequist (2012)
J. Clin. Oncol.
30, 3330-3336
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Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2.
H. Greulich, B. Kaplan, P. Mertins, T.-H. Chen, K. E. Tanaka, C.-H. Yun, X. Zhang, S.-H. Lee, J. Cho, L. Ambrogio, et al. (2012)
PNAS
109, 14476-14481
|Abstract »|Full Text »|PDF »
Molecular Pathology of Non-Small Cell Lung Cancer: A Practical Guide.
Epidermal Growth Factor Receptor Gene Analysis With a Highly Sensitive Molecular Assay in Routine Cytologic Specimens of Lung Adenocarcinoma.
S. Allegrini, J. Antona, R. Mezzapelle, U. Miglio, A. Paganotti, C. Veggiani, M. Frattini, G. Monga, P. Balbo, and R. Boldorini (2012)
Am J Clin Pathol
138, 377-381
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Influence of Chemotherapy on EGFR Mutation Status Among Patients With Non-Small-Cell Lung Cancer.
H. Bai, Z. Wang, K. Chen, J. Zhao, J. J. Lee, S. Wang, Q. Zhou, M. Zhuo, L. Mao, T. An, et al. (2012)
J. Clin. Oncol.
30, 3077-3083
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Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1.
L. A. Byers, J. Wang, M. B. Nilsson, J. Fujimoto, P. Saintigny, J. Yordy, U. Giri, M. Peyton, Y. H. Fan, L. Diao, et al. (2012)
Cancer Discovery
2, 798-811
|Abstract »|Full Text »|PDF »
Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402).
S. Niho, Y. Ohe, S. Ishikura, S. Atagi, A. Yokoyama, Y. Ichinose, H. Okamoto, K. Takeda, T. Shibata, T. Tamura, et al. (2012)
Ann. Onc.
23, 2253-2258
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KRASG12D- and BRAFV600E-Induced Transformation of Murine Pancreatic Epithelial Cells Requires MEK/ERK-Stimulated IGF1R Signaling.
V. A. Appleman, L. G. Ahronian, J. Cai, D. S. Klimstra, and B. C. Lewis (2012)
Mol. Cancer Res.
10, 1228-1239
|Abstract »|Full Text »|PDF »
Epidermal growth factor receptor (EGFR) inhibitors and derived treatments.
First-Line Erlotinib Followed by Second-Line Cisplatin-Gemcitabine Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The TORCH Randomized Trial.
C. Gridelli, F. Ciardiello, C. Gallo, R. Feld, C. Butts, V. Gebbia, P. Maione, F. Morgillo, G. Genestreti, A. Favaretto, et al. (2012)
J. Clin. Oncol.
30, 3002-3011
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Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non-Small Cell Lung Cancer: Identification of a FIG-ROS1 Fusion.
V. M. Rimkunas, K. E. Crosby, D. Li, Y. Hu, M. E. Kelly, T.-L. Gu, J. S. Mack, M. R. Silver, X. Zhou, and H. Haack (2012)
Clin. Cancer Res.
18, 4449-4457
|Abstract »|Full Text »|PDF »
The Impact of Initial Gefitinib or Erlotinib versus Chemotherapy on Central Nervous System Progression in Advanced Non-Small Cell Lung Cancer with EGFR Mutations.
S. Heon, B. Y. Yeap, N. I. Lindeman, V. A. Joshi, M. Butaney, G. J. Britt, D. B. Costa, M. S. Rabin, D. M. Jackman, and B. E. Johnson (2012)
Clin. Cancer Res.
18, 4406-4414
|Abstract »|Full Text »|PDF »
Network-based drug discovery by integrating systems biology and computational technologies.
E. L. Leung, Z.-W. Cao, Z.-H. Jiang, H. Zhou, and L. Liu (2012)
Brief Bioinform
|Abstract »|Full Text »|PDF »
Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer.
Y. Jeong, Y. Xie, W. Lee, A. L. Bookout, L. Girard, G. Raso, C. Behrens, I. I. Wistuba, A. F. Gadzar, J. D. Minna, et al. (2012)
Mol. Endocrinol.
26, 1443-1454
|Abstract »|Full Text »|PDF »
Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.
K. Ohashi, L. V. Sequist, M. E. Arcila, T. Moran, J. Chmielecki, Y.-L. Lin, Y. Pan, L. Wang, E. de Stanchina, K. Shien, et al. (2012)
PNAS
109, E2127-E2133
|Abstract »|Full Text »|PDF »
Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model.
H. Herranz, X. Hong, N. T. Hung, P. M. Voorhoeve, and S. M. Cohen (2012)
Genes & Dev.
26, 1602-1611
|Abstract »|Full Text »|PDF »
Ultrasensitive Measurement of Hotspot Mutations in Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep Sequencing.
A. Narayan, N. J. Carriero, S. N. Gettinger, J. Kluytenaar, K. R. Kozak, T. I. Yock, N. E. Muscato, P. Ugarelli, R. H. Decker, and A. A. Patel (2012)
Cancer Res.
72, 3492-3498
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EGFR and K-ras mutations in cytologic samples from fine-needle aspirates in NSCLC patients.
P. Ulivi, W. Zoli, E. Chiadini, L. Capelli, P. Candoli, D. Calistri, R. Silvestrini, and M. Puccetti (2012)
Eur. Respir. J.
40, 267-269
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Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer.
L. Leung, T. S. K. Mok, and H. Loong (2012)
Therapeutic Advances in Medical Oncology
4, 173-181
|Abstract »|PDF »
Combined EGFR/MET or EGFR/HSP90 Inhibition Is Effective in the Treatment of Lung Cancers Codriven by Mutant EGFR Containing T790M and MET.
L. Xu, E. Kikuchi, C. Xu, H. Ebi, D. Ercan, K. A. Cheng, R. Padera, J. A. Engelman, P. A. Janne, G. I. Shapiro, et al. (2012)
Cancer Res.
72, 3302-3311
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Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas'.
B. Yan and G. S. D. Lim (2012)
J. Clin. Pathol.
65, 671-672
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Complex Role of Histone Deacetylase Inhibitors in the Treatment of Non-Small-Cell Lung Cancer.
J. W. Neal and L. V. Sequist (2012)
J. Clin. Oncol.
30, 2280-2282
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Clinical Outcomes in Non-Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR.
K.-P. Chung, S.-G. Wu, J.-Y. Wu, J. C.-H. Yang, C.-J. Yu, P.-F. Wei, J.-Y. Shih, and P.-C. Yang (2012)
Clin. Cancer Res.
18, 3470-3477
|Abstract »|Full Text »|PDF »
Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial.
P. A. Janne, X. Wang, M. A. Socinski, J. Crawford, T. E. Stinchcombe, L. Gu, M. Capelletti, M. J. Edelman, M. A. Villalona-Calero, R. Kratzke, et al. (2012)
J. Clin. Oncol.
30, 2063-2069
|Abstract »|Full Text »|PDF »
catalytic subunit gene PIK3CA in human colorectal carcinoma (6, 7). 
To whom correspondence should be addressed. E-mail: 
CGG; L858R). 
50% tumor regression in a computed tomography scan after 2 months of treatment), whereas the fifth patient experienced dramatic symptomatic improvement in less than 2 months. All of the patients were from the United States and were Caucasian. 
