Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells

J. Tanizaki, I. Okamoto, K. Takezawa, K. Sakai, K. Azuma, K. Kuwata, H. Yamaguchi, E. Hatashita, K. Nishio, P. A. Janne, K. Nakagawa

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.

Original languageEnglish
Pages (from-to)763-767
Number of pages5
JournalBritish journal of cancer
Volume106
Issue number4
DOIs
Publication statusPublished - Feb 14 2012

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Non-Small Cell Lung Carcinoma
MAP Kinase Signaling System
Apoptosis
Phosphorylation
Cell Proliferation
MAP4
anaplastic lymphoma kinase
Gene Fusion
Protein-Tyrosine Kinases
Signal Transduction
Up-Regulation
Down-Regulation
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. / Tanizaki, J.; Okamoto, I.; Takezawa, K.; Sakai, K.; Azuma, K.; Kuwata, K.; Yamaguchi, H.; Hatashita, E.; Nishio, K.; Janne, P. A.; Nakagawa, K.

In: British journal of cancer, Vol. 106, No. 4, 14.02.2012, p. 763-767.

Research output: Contribution to journalArticle

Tanizaki, J, Okamoto, I, Takezawa, K, Sakai, K, Azuma, K, Kuwata, K, Yamaguchi, H, Hatashita, E, Nishio, K, Janne, PA & Nakagawa, K 2012, 'Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells', British journal of cancer, vol. 106, no. 4, pp. 763-767. https://doi.org/10.1038/bjc.2011.586
Tanizaki, J. ; Okamoto, I. ; Takezawa, K. ; Sakai, K. ; Azuma, K. ; Kuwata, K. ; Yamaguchi, H. ; Hatashita, E. ; Nishio, K. ; Janne, P. A. ; Nakagawa, K. / Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. In: British journal of cancer. 2012 ; Vol. 106, No. 4. pp. 763-767.
@article{5cc99d22698d4fc29666367f445b39e9,
title = "Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells",
abstract = "BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.",
author = "J. Tanizaki and I. Okamoto and K. Takezawa and K. Sakai and K. Azuma and K. Kuwata and H. Yamaguchi and E. Hatashita and K. Nishio and Janne, {P. A.} and K. Nakagawa",
year = "2012",
month = "2",
day = "14",
doi = "10.1038/bjc.2011.586",
language = "English",
volume = "106",
pages = "763--767",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells

AU - Tanizaki, J.

AU - Okamoto, I.

AU - Takezawa, K.

AU - Sakai, K.

AU - Azuma, K.

AU - Kuwata, K.

AU - Yamaguchi, H.

AU - Hatashita, E.

AU - Nishio, K.

AU - Janne, P. A.

AU - Nakagawa, K.

PY - 2012/2/14

Y1 - 2012/2/14

N2 - BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.

AB - BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.

UR - http://www.scopus.com/inward/record.url?scp=84856915008&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856915008&partnerID=8YFLogxK

U2 - 10.1038/bjc.2011.586

DO - 10.1038/bjc.2011.586

M3 - Article

C2 - 22240786

AN - SCOPUS:84856915008

VL - 106

SP - 763

EP - 767

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 4

ER -