Reference Detail

Ref Type

Journal Article

PMID

(38885476)

Authors

Vanoli F, Song E, Dermawan JK, Fishinevich E, Sung P, Min SS, Xie Z, de Traux de Wardin H, Hwang S, Maki RG, Antonescu CR

Title

Modeling Extraordinary Response Through Targeting Secondary Alterations in Fusion-Associated Sarcoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	8		2024 Jun	e2300688	JCO Precis Oncol

URL

Abstract Text

Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes (TP53, CDKN2A/B). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary BRAF V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical EWSR1::CREB1 fusion.The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and followed a highly aggressive clinical course, with rapid multifocal local recurrence within a year and widespread distant metastases (adrenal, bone, liver, lung). The tumor showed characteristic morphologic features, with histiocytoid cells intermixed with hemorrhagic cystic spaces and lymphoid aggregates. In addition to the pathognomonic EWSR1::CREB1 fusion, targeted DNA sequencing revealed in both primary and adrenal metastatic sites a hot spot BRAF V600E mutation and a CDKN2A/B deletion. Accordingly, the patient was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) showing an excellent but short-lived response.Using a CRISPR-Cas9 approach, we introduced the BRAF c.1799 T>A point mutation in human embryonic stem (hES) cells harboring a conditional EWSR1 (exon7)::CREB1 (exon7) translocation and further differentiated to mesenchymal progenitors (hES-MP) before fusion expression. The cells maintained the fusion transcript expression and the AFH core gene signature while responding to treatment with encorafenib and binimetinib.These results highlight that additional targeted DNA NGS in chemotherapy-resistant translocation-associated sarcomas may reveal actionable oncogenic drivers occurring as secondary genetic events during disease progression.

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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
BRAF V600E	malignant fibrous histiocytoma	sensitive	Binimetinib + Encorafenib	Case Reports/Case Series	Actionable	In a clinical case study, treatment with the combination of Mektovi (binimetinib) and Braftovi (encorafenib) resulted in a clinical response after two months in a patient with angiomatoid fibrous histiocytoma harboring BRAF V600E, along with EWSR1-CREB1 (e7:e7), and in a preclinical study, combination treatment with Mektovi (binimetinib) and Braftovi (encorafenib) inhibited viability of cells in culture (PMID: 38885476).	38885476