Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors.
The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non-small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4-ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor.
Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA.
Yongjun
Y
Li
Xiaofen
X
Ye
Jinfeng
J
Liu
Jiping
J
Zha
Lin
L
Pei
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D019394:Ki-67 Antigen; C516714:NVP-TAE684; D015514:Oncogene Proteins, Fusion; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
Neoplasia. 2008 Mar;10(3):298-302
18320074
Science. 1999 Jul 16;285(5426):418-22
10411507
Cell. 2007 Dec 14;131(6):1190-203
18083107
Curr Opin Genet Dev. 1996 Apr;6(2):208-14
8722178
Clin Cancer Res. 2008 Jul 1;14(13):4275-83
18594010
Mol Endocrinol. 1997 Apr;11(4):433-41
9092795
Mol Cell Biol. 1995 May;15(5):2612-24
7739542
J Immunol. 2002 Jan 1;168(1):466-74
11751994
J Clin Pathol. 2007 Jul;60(7):768-72
16882699
Genome Biol. 2004;5(10):R80
15461798
J Biol Chem. 2007 Jun 1;282(22):16336-44
17403684
Cancer Res. 1992 Jan 1;52(1):231-4
1309226
Am J Pathol. 2000 Jan;156(1):217-25
10623670
Cancer Res. 2007 Mar 15;67(6):2893-8
17363613
Blood. 1999 Aug 15;94(4):1348-58
10438723
Oncogene. 2001 Sep 10;20(40):5623-37
11607814
Cancer Res. 2008 May 1;68(9):3389-95
18451166
Cancer Res. 2007 May 1;67(9):4408-17
17483355
Blood. 2003 Mar 1;101(5):1919-27
12424201
Leukemia. 2005 Jul;19(7):1128-34
15902287
Clin Cancer Res. 2009 Sep 15;15(18):5609-14
19737948
Clin Cancer Res. 2006 Feb 15;12(4):1184-91
16489072
Blood. 1997 Oct 15;90(8):2901-10
9376569
Breast Cancer Res Treat. 2007 Dec;106(2):181-9
17260090
Proteomics. 2005 Aug;5(13):3226-45
16104056
Blood. 2007 Oct 1;110(7):2259-67
17519389
Blood. 2006 Feb 15;107(4):1617-23
16254137
Mol Cell. 2008 Nov 7;32(3):394-405
18995837
Mol Cancer Ther. 2005 Jun;4(6):876-84
15956245
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8686-98
16361555
Blood. 2006 Jan 15;107(2):689-97
16189272
Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3314-22
18089725
Cell Cycle. 2007 Dec 15;6(24):3114-31
18075315
Cancer Res. 2008 Jul 1;68(13):4971-6
18593892
Nature. 2007 Aug 2;448(7153):561-6
17625570
Clin Cancer Res. 2009 May 1;15(9):3143-9
19383809
Science. 1994 Mar 4;263(5151):1281-4
8122112
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19893-7
19064915
Cancer. 2009 Apr 15;115(8):1723-33
19170230
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5
17185414
Int J Biol Markers. 2007 Apr-Jun;22(2):108-13
17549666