Reference Detail

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 Mar 14	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, but 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 not transforming in culture, but 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 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 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
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	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