RAS pathway targeted therapy in patients with DICER1-associated sarcomas
Abstract DICER1-associated sarcomas commonly exhibit cooperating mutations involving RAS signaling pathways, but the efficacy of therapies that target these mutations is unknown. Here we report two children with DICER1 tumor predisposition who presented with DICER1-associated sarcomas with cooperati...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01026-0 |
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| author | Lindy Zhang Paige H. R. Mallinger Serena Zhou Stavriani C. Makri John M. Gross Calixto-Hope G. Lucas Ying S. Zou William Mize Damon R. Olson Senna R. Munnikhuysen Jawhar Rawwas Yoav Messinger Kenneth S. Chen Kris Ann P. Schultz Christine A. Pratilas |
| author_facet | Lindy Zhang Paige H. R. Mallinger Serena Zhou Stavriani C. Makri John M. Gross Calixto-Hope G. Lucas Ying S. Zou William Mize Damon R. Olson Senna R. Munnikhuysen Jawhar Rawwas Yoav Messinger Kenneth S. Chen Kris Ann P. Schultz Christine A. Pratilas |
| author_sort | Lindy Zhang |
| collection | DOAJ |
| description | Abstract DICER1-associated sarcomas commonly exhibit cooperating mutations involving RAS signaling pathways, but the efficacy of therapies that target these mutations is unknown. Here we report two children with DICER1 tumor predisposition who presented with DICER1-associated sarcomas with cooperating, targetable mutations in HRAS or BRAF. Both had relapsed/progressed disease despite upfront multimodal therapy and were subsequently treated with molecularly targeted agents. In the first case, mutant BRAF became amplified after dual dabrafenib/trametinib therapy, presumably as a driver of acquired resistance. In the second case, a subclonal HRAS variant at diagnosis became the predominant clone at autopsy, suggesting its importance in therapy resistance. Together, these two cases provide molecular evidence of the significance of RAS/ERK signaling in DICER1-driven tumorigenesis and highlight the potential for targeting these cooperating mutations. |
| format | Article |
| id | doaj-art-c53e5cd8176d4b43a93159d95052684c |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-c53e5cd8176d4b43a93159d95052684c2025-08-20T04:01:47ZengNature Portfolionpj Precision Oncology2397-768X2025-07-01911710.1038/s41698-025-01026-0RAS pathway targeted therapy in patients with DICER1-associated sarcomasLindy Zhang0Paige H. R. Mallinger1Serena Zhou2Stavriani C. Makri3John M. Gross4Calixto-Hope G. Lucas5Ying S. Zou6William Mize7Damon R. Olson8Senna R. Munnikhuysen9Jawhar Rawwas10Yoav Messinger11Kenneth S. Chen12Kris Ann P. Schultz13Christine A. Pratilas14Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineCancer and Blood Disorders, Children’s MinnesotaDepartment of Pediatrics, University of Texas Southwestern Medical CenterDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Radiology, Children’s MinnesotaDepartment of Pathology and Laboratory Medicine, Children’s MinnesotaDepartment of Pediatrics, University of KentuckyCancer and Blood Disorders, Children’s MinnesotaCancer and Blood Disorders, Children’s MinnesotaDepartment of Pediatrics, University of Texas Southwestern Medical CenterCancer and Blood Disorders, Children’s MinnesotaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineAbstract DICER1-associated sarcomas commonly exhibit cooperating mutations involving RAS signaling pathways, but the efficacy of therapies that target these mutations is unknown. Here we report two children with DICER1 tumor predisposition who presented with DICER1-associated sarcomas with cooperating, targetable mutations in HRAS or BRAF. Both had relapsed/progressed disease despite upfront multimodal therapy and were subsequently treated with molecularly targeted agents. In the first case, mutant BRAF became amplified after dual dabrafenib/trametinib therapy, presumably as a driver of acquired resistance. In the second case, a subclonal HRAS variant at diagnosis became the predominant clone at autopsy, suggesting its importance in therapy resistance. Together, these two cases provide molecular evidence of the significance of RAS/ERK signaling in DICER1-driven tumorigenesis and highlight the potential for targeting these cooperating mutations.https://doi.org/10.1038/s41698-025-01026-0 |
| spellingShingle | Lindy Zhang Paige H. R. Mallinger Serena Zhou Stavriani C. Makri John M. Gross Calixto-Hope G. Lucas Ying S. Zou William Mize Damon R. Olson Senna R. Munnikhuysen Jawhar Rawwas Yoav Messinger Kenneth S. Chen Kris Ann P. Schultz Christine A. Pratilas RAS pathway targeted therapy in patients with DICER1-associated sarcomas npj Precision Oncology |
| title | RAS pathway targeted therapy in patients with DICER1-associated sarcomas |
| title_full | RAS pathway targeted therapy in patients with DICER1-associated sarcomas |
| title_fullStr | RAS pathway targeted therapy in patients with DICER1-associated sarcomas |
| title_full_unstemmed | RAS pathway targeted therapy in patients with DICER1-associated sarcomas |
| title_short | RAS pathway targeted therapy in patients with DICER1-associated sarcomas |
| title_sort | ras pathway targeted therapy in patients with dicer1 associated sarcomas |
| url | https://doi.org/10.1038/s41698-025-01026-0 |
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