MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib

James Bean, Cameron Brennan, Jin Yuan Shih, Gregory Riely, Agnes Viale, Lu Wang, Dhananjay Chitale, Noriko Motoi, Janos Szoke, Stephen Broderick, Marissa Balak, Wen Cheng Chang, Chong Jen Yu, Adi Gazdar, Harvey Pass, Valerie Rusch, William Gerald, Shiu Feng Huang, Pan Chyr Yang, Vincent Miller & 3 others Marc Ladanyi, Chih Hsin Yang, William Pao

Research output: Contribution to journalArticle

Abstract

In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFRT790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

Original languageEnglish (US)
Pages (from-to)20932-20937
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number52
DOIs
StatePublished - Dec 26 2007
Externally publishedYes

Fingerprint

Lung
Mutation
Neoplasms
Comparative Genomic Hybridization
Proto-Oncogenes
Threonine
gefitinib
Erlotinib Hydrochloride
Point Mutation
Methionine
Disease Progression
Phosphotransferases
Cell Line
Growth
Pharmaceutical Preparations
Adenocarcinoma of lung
Therapeutics

Keywords

  • Lung adenocarcinoma
  • XL880

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. / Bean, James; Brennan, Cameron; Shih, Jin Yuan; Riely, Gregory; Viale, Agnes; Wang, Lu; Chitale, Dhananjay; Motoi, Noriko; Szoke, Janos; Broderick, Stephen; Balak, Marissa; Chang, Wen Cheng; Yu, Chong Jen; Gazdar, Adi; Pass, Harvey; Rusch, Valerie; Gerald, William; Huang, Shiu Feng; Yang, Pan Chyr; Miller, Vincent; Ladanyi, Marc; Yang, Chih Hsin; Pao, William.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 52, 26.12.2007, p. 20932-20937.

Research output: Contribution to journalArticle

Bean, J, Brennan, C, Shih, JY, Riely, G, Viale, A, Wang, L, Chitale, D, Motoi, N, Szoke, J, Broderick, S, Balak, M, Chang, WC, Yu, CJ, Gazdar, A, Pass, H, Rusch, V, Gerald, W, Huang, SF, Yang, PC, Miller, V, Ladanyi, M, Yang, CH & Pao, W 2007, 'MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 52, pp. 20932-20937. https://doi.org/10.1073/pnas.0710370104
Bean, James ; Brennan, Cameron ; Shih, Jin Yuan ; Riely, Gregory ; Viale, Agnes ; Wang, Lu ; Chitale, Dhananjay ; Motoi, Noriko ; Szoke, Janos ; Broderick, Stephen ; Balak, Marissa ; Chang, Wen Cheng ; Yu, Chong Jen ; Gazdar, Adi ; Pass, Harvey ; Rusch, Valerie ; Gerald, William ; Huang, Shiu Feng ; Yang, Pan Chyr ; Miller, Vincent ; Ladanyi, Marc ; Yang, Chih Hsin ; Pao, William. / MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 52. pp. 20932-20937.
@article{19d0cda684fa4dc489449a6a8d149759,
title = "MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib",
abstract = "In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21{\%}) patients with acquired resistance but in only two tumors from 62 untreated patients (3{\%}) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFRT790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.",
keywords = "Lung adenocarcinoma, XL880",
author = "James Bean and Cameron Brennan and Shih, {Jin Yuan} and Gregory Riely and Agnes Viale and Lu Wang and Dhananjay Chitale and Noriko Motoi and Janos Szoke and Stephen Broderick and Marissa Balak and Chang, {Wen Cheng} and Yu, {Chong Jen} and Adi Gazdar and Harvey Pass and Valerie Rusch and William Gerald and Huang, {Shiu Feng} and Yang, {Pan Chyr} and Vincent Miller and Marc Ladanyi and Yang, {Chih Hsin} and William Pao",
year = "2007",
month = "12",
day = "26",
doi = "10.1073/pnas.0710370104",
language = "English (US)",
volume = "104",
pages = "20932--20937",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "52",

}

TY - JOUR

T1 - MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib

AU - Bean, James

AU - Brennan, Cameron

AU - Shih, Jin Yuan

AU - Riely, Gregory

AU - Viale, Agnes

AU - Wang, Lu

AU - Chitale, Dhananjay

AU - Motoi, Noriko

AU - Szoke, Janos

AU - Broderick, Stephen

AU - Balak, Marissa

AU - Chang, Wen Cheng

AU - Yu, Chong Jen

AU - Gazdar, Adi

AU - Pass, Harvey

AU - Rusch, Valerie

AU - Gerald, William

AU - Huang, Shiu Feng

AU - Yang, Pan Chyr

AU - Miller, Vincent

AU - Ladanyi, Marc

AU - Yang, Chih Hsin

AU - Pao, William

PY - 2007/12/26

Y1 - 2007/12/26

N2 - In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFRT790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

AB - In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFRT790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

KW - Lung adenocarcinoma

KW - XL880

UR - http://www.scopus.com/inward/record.url?scp=38049150665&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38049150665&partnerID=8YFLogxK

U2 - 10.1073/pnas.0710370104

DO - 10.1073/pnas.0710370104

M3 - Article

VL - 104

SP - 20932

EP - 20937

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 52

ER -