1. Department of Pediatric Oncology,
2. Department of Medical Oncology & Center for Cancer Genome Discovery, and,
3. Department of Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
5. Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
6. Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida 32601, USA
7. Departments of Pathology and Oncology, and,
8. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
9. ChemBridge Research Laboratories Inc., San Diego, California 92127, USA
10. These authors contributed equally to this work.

Correspondence to: Matthew Meyerson^2,4A. Thomas Look¹ Correspondence and requests for materials should be addressed to A.T.L. (Email: thomas_look@dfci.harvard.edu) or M.M. (Email: matthew_meyerson@dfci.harvard.edu).

Abstract

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer¹. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal^{2, 3}. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.

1. Department of Pediatric Oncology,
2. Department of Medical Oncology & Center for Cancer Genome Discovery, and,
3. Department of Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
5. Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
6. Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida 32601, USA
7. Departments of Pathology and Oncology, and,
8. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
9. ChemBridge Research Laboratories Inc., San Diego, California 92127, USA
10. These authors contributed equally to this work.

Correspondence to: Matthew Meyerson^2,4A. Thomas Look¹ Correspondence and requests for materials should be addressed to A.T.L. (Email: thomas_look@dfci.harvard.edu) or M.M. (Email: matthew_meyerson@dfci.harvard.edu).

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