Activating mutations in ALK provide a therapeutic target in neuroblastoma

By R. George, T. Sanda, M. Hanna, S. Fröhling, William Luther Ii, Jianming Zhang, Yebin Ahn, Wenjun Zhou, W. London, Patrick W. McGrady and 11 more. Nature, 2008

895 citations recorded by the source corpus.

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. 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.

Subfields: Cancer Research, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/bf89ecb712d8daa4521cc5f401aab4668a47cefb

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Citations in the corpus

Neuroblastoma and MYCN (2013, background): “Gain of function mutations in the receptor tyrosine kinase ALK (chromosome 2p23) occur in 50% of familial neuroblastoma cases, and 7% of sporadic neuroblastoma cases (Chen et al. 2008; George et al. 2008; Janoueix-Lerosey et al. 2008; Mossé et al. 2008; Molenaaret al. 2012b).”
A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations (2018, background): “Such ALK mutations have been shown to hyperactivate the RAS–MAPK signaling pathway in NBL, driving cancer formation (17).”
Unique Clinicopathologic Features Characterize ALK-rearranged Lung Adenocarcinoma in the Western Population (2009, background): “Since their discovery in ALCL, ALK rearrangements or mutations have been identified in inflammatory myofibroblastic tumors, a subset of diffuse large B-cell lymphomas (42–45), and a subset of neuroblastomas (46, 47).”
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer (2010, neutral): “of patients (%) Any adverse event† Nausea 43 (52) 1 (1) 0 0 44 (54) Diarrhea 38 (46) 1 (1) 0 0 39 (48) Vomiting 35 (43) 1 (1) 0 0 36 (44) Visual disturbance 34 (41) 0 0 0 34 (41) Constipation 18 (22) 2 (2) 0 0 20 (24) Peripheral edema 13 (16) 0 0 0 13 (16) Dizziness 12 (15) 0 0 0 12 (15) Decreased a”
Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset (2015, neutral): “Consistent with this hypothesis, cotreatment with crizotinib plus BMS-754807 significantly shifted the IC50 compared with crizotinib or BMS-754807 alone in the NB1 CCL, as did cotreatment with NVP-TAE684 plus BMS-754807 (Fig.”