Reference Detail

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 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 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 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 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 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 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
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 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