Modeling extraordinary response through targeting secondary alterations in fusion-associated sarcoma Journal Article
| Authors: | Vanoli, F.; Song, E.; Dermawan, J. K.; Fishinevich, E.; Sung, P.; Min, S. S.; Xie, Z.; de Traux de Wardin, H.; Hwang, S.; Maki, R. G.; Antonescu, C. R. |
| Article Title: | Modeling extraordinary response through targeting secondary alterations in fusion-associated sarcoma |
| Abstract: | PURPOSE 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. MATERIALS The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and AND METHODS 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. RESULTS 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. CONCLUSION 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. © 2024 by American Society of Clinical Oncology. |
| Keywords: | adult; clinical article; human cell; disease course; case report; follow up; polymerase chain reaction; reverse transcription polymerase chain reaction; distant metastasis; sarcoma; cell transformation; western blotting; upregulation; single stranded dna; disease exacerbation; institutional review; histiocytoma; angiomatoid fibrous histiocytoma; mitogen activated protein kinase kinase inhibitor; dna sequencing; human; female; article; rna sequencing; binimetinib; gene set enrichment analysis; encorafenib; whole transcriptome sequencing; apoptosis assay; core gene; fusion associated sarcoma |
| Journal Title: | JCO Precision Oncology |
| Volume: | 8 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2024-09-01 |
| Start Page: | e2300688 |
| Language: | English |
| DOI: | 10.1200/po.23.00688 |
| PUBMED: | 38885476 |
| PROVIDER: | scopus |
| PMCID: | PMC11529323 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF; MSK corresponding author is Fabio Vanoli -- Source: Scopus |
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