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Ref Type Journal Article
PMID (38531265)
Authors Lippai Z, Péterfia B, Papp G, Dezső K, Bedics G, Pápai Z, Lamers MH, Kuin RC, Szuhai K, Sápi Z
Title A recurrent NTRK1 tyrosine kinase domain mutation pair is characteristic in a subset of dedifferentiated liposarcomas.
Journal Vol Issue Date Pages Journal Short Title
European journal of cancer (Oxford, England : 1990) 202 2024 May 114005 Eur J Cancer
URL
Abstract Text Dedifferentiated liposarcoma (DDLPS) is a common form of liposarcoma with challenging treatment modalities. Pan-TRK immunopositivity can be often observed without NTRK gene fusion in soft tissue sarcomas with myogenic differentiation. Expression and the role of NTRK in DDLPS are under-studied. We sought to identify activating mutations of the NTRK genes.131 DDLPS patients were selected for pan-TRK immunohistochemistry and positive cases were analyzed by Sanger sequencing for NTRK1, NTRK2 and NTRK3 genes. Functional assays were performed using a lentiviral transduction system to study the effect of NTRK variants in fibroblast, immortalized fibroblast, and dedifferentiated liposarcoma cell lines.Out of the 131 DDLPS cases, 75 immunohistochemical staining positive cases, 46 were successfully Sanger sequenced. A recurrent somatic mutation pair in cis position (NGS) of the NTRK1 c.1810C>T (p.H604Y) and c.1838G>T (p.G613V) was identified in six cases (13%) that have never been reported in DDLPS. NTRK fusions were excluded in all six cases by FISH and NGS. The phospho-AKT immunopositivity among the six mutated cases suggested downstream activation of the NTRK signaling pathway. Functional assays showed no transforming effects, but resistance to first- and second-line TRK inhibitors of the p.G613V and p.H604Y variant.We detected (de novo/somatic) missense mutation variants in cis position of the NTRK1 gene in a subset of DDLPS indicating modifying mutations that may contribute to tumorigenesis in a subset of DDLPS. These variants beget resistance to TRK inhibitors indicating an interesting biomarker for other studies with TRK inhibitors.

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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
NTRK1 G613V missense unknown NTRK1 G613V lies within the protein kinase domain of the Ntrk1 protein (UniProt.org). G613V is not transforming in culture, results in increased phosphorylation of Akt in combination with NTRK1 H604Y in patient samples, and has been associated with resistance to NTRK inhibitors in cell culture (PMID: 38531265), but has not been individually biochemically characterized and therefore, its effect on Nrtk1 protein function is unknown. Y
NTRK1 H604Y missense unknown NTRK1 H604Y lies within the protein kinase domain of the Ntrk1 protein (UniProt.org). H604Y is a common Ntrk1 polymorphism (PMID: 20003389, PMID: 38531265), and is not transforming in culture, results in increased phosphorylation of Akt in combination with NTRK1 G613V in patient samples, and has been associated with resistance to NTRK inhibitors in cell culture (PMID: 38531265), but has not been individually biochemically characterized and therefore, its effect on Ntrk1 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK1 G613V dedifferentiated liposarcoma resistant Larotrectinib Preclinical - Cell culture Actionable In a preclinical study, a dedifferentiated liposarcoma cell line expressing NTRK1 G613V demonstrated resistance to Vitrakvi (larotrectinib) in culture (PMID: 38531265). 38531265
NTRK1 H604Y NTRK1 G613V dedifferentiated liposarcoma resistant Selitrectinib Preclinical - Cell culture Actionable In a preclinical study, a dedifferentiated liposarcoma cell line expressing NTRK1 G613V and H604Y demonstrated resistance to Selitrectinib (LOXO-195) in culture (PMID: 38531265). 38531265
NTRK1 H604Y NTRK1 G613V dedifferentiated liposarcoma resistant Larotrectinib Preclinical - Cell culture Actionable In a preclinical study, a dedifferentiated liposarcoma cell line expressing NTRK1 G613V and H604Y demonstrated resistance to Vitrakvi (larotrectinib) in culture (PMID: 38531265). 38531265
NTRK1 G613V dedifferentiated liposarcoma resistant Selitrectinib Preclinical - Cell culture Actionable In a preclinical study, a dedifferentiated liposarcoma cell line expressing NTRK1 G613V demonstrated resistance to Selitrectinib (LOXO-195) in culture (PMID: 38531265). 38531265