Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Kadoaki Oohashi, Lecia V. Sequist, Maria E. Arcila, Teresa Moran, Juliann Chmielecki, Ya Lun Lin, Yumei Pan, Lu Wang, Elisa De Stanchina, Kazuhiko Shien, Keisuke Aoe, Shinichi Toyooka, Katsuyuki Kiura, Lynnette Fernandez-Cuesta, Panos Fidias, James Chih Hsin Yang, Vincent A. Miller, Gregory J. Riely, Mark G. Kris, Jeffrey A. Engelman & 4 others Cindy L. Vnencak-Jones, Dora Dias-Santagata, Marc Ladanyi, William Pao

Research output: Contribution to journalArticle

294 Citations (Scopus)

Abstract

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number31
DOIs
Publication statusPublished - Jul 31 2012

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Epidermal Growth Factor Receptor
Lung Neoplasms
Mutation
Protein-Tyrosine Kinases
Genes
Mitogen-Activated Protein Kinase Kinases
Neoplasms
Gastrointestinal Stromal Tumors
Tumor Cell Line
Colonic Neoplasms
Disease Progression
Melanoma
Therapeutics
Clinical Trials
Pharmaceutical Preparations

Keywords

  • Erlotinib
  • Gefitinib
  • Nras mutation

ASJC Scopus subject areas

  • General

Cite this

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. / Oohashi, Kadoaki; Sequist, Lecia V.; Arcila, Maria E.; Moran, Teresa; Chmielecki, Juliann; Lin, Ya Lun; Pan, Yumei; Wang, Lu; De Stanchina, Elisa; Shien, Kazuhiko; Aoe, Keisuke; Toyooka, Shinichi; Kiura, Katsuyuki; Fernandez-Cuesta, Lynnette; Fidias, Panos; Yang, James Chih Hsin; Miller, Vincent A.; Riely, Gregory J.; Kris, Mark G.; Engelman, Jeffrey A.; Vnencak-Jones, Cindy L.; Dias-Santagata, Dora; Ladanyi, Marc; Pao, William.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 31, 31.07.2012.

Research output: Contribution to journalArticle

Oohashi, K, Sequist, LV, Arcila, ME, Moran, T, Chmielecki, J, Lin, YL, Pan, Y, Wang, L, De Stanchina, E, Shien, K, Aoe, K, Toyooka, S, Kiura, K, Fernandez-Cuesta, L, Fidias, P, Yang, JCH, Miller, VA, Riely, GJ, Kris, MG, Engelman, JA, Vnencak-Jones, CL, Dias-Santagata, D, Ladanyi, M & Pao, W 2012, 'Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 31. https://doi.org/10.1073/pnas.1203530109
Oohashi, Kadoaki ; Sequist, Lecia V. ; Arcila, Maria E. ; Moran, Teresa ; Chmielecki, Juliann ; Lin, Ya Lun ; Pan, Yumei ; Wang, Lu ; De Stanchina, Elisa ; Shien, Kazuhiko ; Aoe, Keisuke ; Toyooka, Shinichi ; Kiura, Katsuyuki ; Fernandez-Cuesta, Lynnette ; Fidias, Panos ; Yang, James Chih Hsin ; Miller, Vincent A. ; Riely, Gregory J. ; Kris, Mark G. ; Engelman, Jeffrey A. ; Vnencak-Jones, Cindy L. ; Dias-Santagata, Dora ; Ladanyi, Marc ; Pao, William. / Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 31.
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abstract = "Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1{\%}) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.",
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AU - Oohashi, Kadoaki

AU - Sequist, Lecia V.

AU - Arcila, Maria E.

AU - Moran, Teresa

AU - Chmielecki, Juliann

AU - Lin, Ya Lun

AU - Pan, Yumei

AU - Wang, Lu

AU - De Stanchina, Elisa

AU - Shien, Kazuhiko

AU - Aoe, Keisuke

AU - Toyooka, Shinichi

AU - Kiura, Katsuyuki

AU - Fernandez-Cuesta, Lynnette

AU - Fidias, Panos

AU - Yang, James Chih Hsin

AU - Miller, Vincent A.

AU - Riely, Gregory J.

AU - Kris, Mark G.

AU - Engelman, Jeffrey A.

AU - Vnencak-Jones, Cindy L.

AU - Dias-Santagata, Dora

AU - Ladanyi, Marc

AU - Pao, William

PY - 2012/7/31

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N2 - Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

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