Reference Detail

Ref Type

Journal Article

PMID

(31852910)

Authors

Cervantes-Madrid D, Szydzik J, Lind DE, Borenäs M, Bemark M, Cui J, Palmer RH, Hallberg B

Title

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	9	1	2019 12 18	19353	Sci Rep

URL

Abstract Text

Neuroblastoma is the most commonly diagnosed extracranial tumor in the first year of life. Approximately 9% of neuroblastoma patients present germline or somatic aberrations in the gene encoding for anaplastic lymphoma kinase (ALK). This increases in high-risk neuroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increasing numbers at relapse. Abrogating ALK activity with kinase inhibitors is employed as clinical therapy in malignancies such as non-small cell lung cancer and has shown good results in pediatric inflammatory myofibroblastic tumors and anaplastic large cell lymphomas. A phase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients showed modest results and suggested that further investigation was needed. Continuous development of ALK inhibitors has resulted in the third generation inhibitor repotrectinib (TPX-0005), which targets the active kinase conformations of ALK, ROS1 and TRK receptors. In the present study we investigated the effects of repotrectinib in a neuroblastoma setting in vitro and in vivo. Neuroblastoma cell lines were treated with repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation. PC12 cells transfected with different ALK mutant variants were used to study the efficacy of repotrectinib to block ALK activation/signaling. The in vivo effect of repotrectinib was also analyzed in a neuroblastoma xenograft model. Our results show that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of 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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK G1128A	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK G1128A in culture (PMID: 31852910).	31852910
ALK R1192P	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK R1192P in culture (PMID: 31852910).	31852910
ALK F1174L	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK F1174L in culture (PMID: 31852910).	31852910
ALK Y1278S	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK Y1278S in culture (PMID: 31852910).	31852910
ALK F1174L	neuroblastoma	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) inhibited proliferation of a neuroblastoma cell line harboring ALK F1174L in culture (PMID: 31852910).	31852910
ALK F1245C	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK F1245C in culture (PMID: 31852910).	31852910
ALK F1174V ALK amp	neuroblastoma	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) inhibited downstream signaling and proliferation, and induced apoptosis in a neuroblastoma cell line harboring ALK F1174V and ALK amplification in culture (PMID: 31852910).	31852910
ALK R1275Q	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK R1275Q in culture (PMID: 31852910).	31852910
ALK I1171N	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK I1171N in culture (PMID: 31852910).	31852910