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Ref Type Journal Article
PMID (29907598)
Authors Guan J, Fransson S, Siaw JT, Treis D, Van den Eynden J, Chand D, Umapathy G, Ruuth K, Svenberg P, Wessman S, Shamikh A, Jacobsson H, Gordon L, Stenman J, Svensson PJ, Hansson M, Larsson E, Martinsson T, Palmer RH, Kogner P, Hallberg B
Title Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
Journal Vol Issue Date Pages Journal Short Title
Cold Spring Harbor molecular case studies 4 4 2018 08 Cold Spring Harb Mol Case Stud
URL
Abstract Text Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK F1174L missense gain of function ALK F1174L lies within the protein kinase domain of the Alk protein (UniProt.org). F1174L confers a gain of function to the Alk protein as indicated by constitutive phosphorylation of Alk (PMID: 22072639), transformation activity and increased cell proliferation in culture (PMID: 18923525, PMID: 29533785, PMID: 29907598), and has been demonstrated to occur as a secondary resistance mutation in the context of ALK fusions (PMID: 21030459, PMID: 31452835). Y
ALK I1171T missense gain of function ALK I1171T lies within the protein kinase domain of the Alk protein (UniProt.org). I1171T confers a gain of function on the Alk protein as indicated by ligand-independent autophosphorylation, activation of Erk1/2, and cell transformation (PMID: 29907598), and has been demonstrated to confer drug resistance in the context of ALK fusions in culture (PMID: 27009859). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1174L ALK amp neuroblastoma sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174L in culture (PMID: 29907598). 29907598
ALK F1174L ALK amp neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174L in culture (PMID: 29907598). 29907598
ALK F1174V ALK amp neuroblastoma sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174V in culture (PMID: 29907598). 29907598
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 29907598). 29907598
ALK F1174V ALK amp neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174V in culture (PMID: 29907598). 29907598
ALK I1171T ganglioneuroblastoma predicted - sensitive Ceritinib Case Reports/Case Series Actionable In a clinical case study, Zykadia (ceritinib) treatment resulted in a 43.6% decrease of the primary tumor after 6.5 months of treatment, and complete resolution of metastases at 21 months after initiation of treatment in a pediatric patient with ganglioneuroblastoma harboring ALK I1171T (PMID: 29907598). 29907598
ALK R1275Q neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 29907598). 29907598