Abstract
INTRODUCTION: Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors (TKIs) would have antiproliferative activity against ROS1 translocated non-small-cell lung cancer (NSCLC). METHODS: We selected NSCLC cell lines-A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib. RESULTS: Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1-translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis. CONCLUSIONS: The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC.
| Original language | English |
|---|---|
| Pages (from-to) | 1086-1090 |
| Number of pages | 5 |
| Journal | Journal of Thoracic Oncology |
| Volume | 7 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2012 Jul |
| Externally published | Yes |
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Keywords
- ALK
- Anaplastic lymphoma kinase
- Crizotinib
- Epidermal growth factor receptor
- Kinase inhibitor
- Lung cancer
- Non-small-cell lung cancer
- ROS1
- Tyrosine kinase
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
Cite this
Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. / Yasuda, Hiroyuki; De Figueiredo-Pontes, Lorena L.; Kobayashi, Susumu; Costa, Daniel B.
In: Journal of Thoracic Oncology, Vol. 7, No. 7, 07.2012, p. 1086-1090.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer
AU - Yasuda, Hiroyuki
AU - De Figueiredo-Pontes, Lorena L.
AU - Kobayashi, Susumu
AU - Costa, Daniel B.
PY - 2012/7
Y1 - 2012/7
N2 - INTRODUCTION: Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors (TKIs) would have antiproliferative activity against ROS1 translocated non-small-cell lung cancer (NSCLC). METHODS: We selected NSCLC cell lines-A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib. RESULTS: Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1-translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis. CONCLUSIONS: The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC.
AB - INTRODUCTION: Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors (TKIs) would have antiproliferative activity against ROS1 translocated non-small-cell lung cancer (NSCLC). METHODS: We selected NSCLC cell lines-A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib. RESULTS: Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1-translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis. CONCLUSIONS: The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC.
KW - ALK
KW - Anaplastic lymphoma kinase
KW - Crizotinib
KW - Epidermal growth factor receptor
KW - Kinase inhibitor
KW - Lung cancer
KW - Non-small-cell lung cancer
KW - ROS1
KW - Tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=84862846839&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862846839&partnerID=8YFLogxK
U2 - 10.1097/JTO.0b013e3182570919
DO - 10.1097/JTO.0b013e3182570919
M3 - Article
C2 - 22617245
AN - SCOPUS:84862846839
VL - 7
SP - 1086
EP - 1090
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
IS - 7
ER -