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The UBEC3–LRP5 Fusion is a Novel Oncogenic Driver in Head and Neck Cancer with Therapeutic Implications
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788211
*Corresponding author: (e-mail: adutt@actrec.gov.in).
Abstract
Background: Tissue-agnostic therapies approved for treating gene fusions have substantially reduced the gap between tumor heterogeneity and treatment failure. Head and neck cancer (HNSCC) remains impervious to treatment due to high heterogeneity. Identification of targetable fusion oncogenes may help in the treatment of HNSCC patients regardless of tumor heterogeneity.
Materials and Methods: Performed whole transcriptome sequencing and RT-PCR-based analysis of 151 HNSCC samples for identification and validation of fusion transcripts. To investigate the role of fusion transcript in tumorigenesis, HNSCC cells overexpressing/knockdown of fusion transcript were characterized using in vitro biochemical, genetic approaches, and cell-based assays along with xenograft mouse model.
Results: Identified novel UBE3C–LRP5 fusion in 5.3% of HNSCC patients of Indian origin and 1.2% of TCGA-HNSC patients. We demonstrate that UBE3C–LRP5 fusion overexpression is activating in vitro and in vivo, and promotes proliferation, migration, and invasion of HNSCC cells, whereas its depletion suppresses these phenotypes. UBE3C–LRP5 fusion constitutively activates the Wnt/β-catenin pathway. Consistently, treatment with the FDA-approved drug, pyrvinium pamoate, inhibits the Wnt/β-catenin pathway and reduced the transforming ability of cells and improved survival in mice bearing tumors of fusion-overexpressing cells. Interestingly, fusion-expressing cells upon knockdown of CTNNB1 or LEF1 show reduced proliferation and clonogenic abilities, and reduced sensitivity to pyrvinium pamoate.
Conclusion: Our study suggests that the UBE3C–LRP5 fusion is a promising therapeutic target for head and neck cancer and that pyrvinium pamoate may be a potential drug candidate for treating head and neck cancer harboring this fusion.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: adutt@actrec.gov.in).
Abstract
Background: Tissue-agnostic therapies approved for treating gene fusions have substantially reduced the gap between tumor heterogeneity and treatment failure. Head and neck cancer (HNSCC) remains impervious to treatment due to high heterogeneity. Identification of targetable fusion oncogenes may help in the treatment of HNSCC patients regardless of tumor heterogeneity.
Materials and Methods: Performed whole transcriptome sequencing and RT-PCR-based analysis of 151 HNSCC samples for identification and validation of fusion transcripts. To investigate the role of fusion transcript in tumorigenesis, HNSCC cells overexpressing/knockdown of fusion transcript were characterized using in vitro biochemical, genetic approaches, and cell-based assays along with xenograft mouse model.
Results: Identified novel UBE3C–LRP5 fusion in 5.3% of HNSCC patients of Indian origin and 1.2% of TCGA-HNSC patients. We demonstrate that UBE3C–LRP5 fusion overexpression is activating in vitro and in vivo, and promotes proliferation, migration, and invasion of HNSCC cells, whereas its depletion suppresses these phenotypes. UBE3C–LRP5 fusion constitutively activates the Wnt/β-catenin pathway. Consistently, treatment with the FDA-approved drug, pyrvinium pamoate, inhibits the Wnt/β-catenin pathway and reduced the transforming ability of cells and improved survival in mice bearing tumors of fusion-overexpressing cells. Interestingly, fusion-expressing cells upon knockdown of CTNNB1 or LEF1 show reduced proliferation and clonogenic abilities, and reduced sensitivity to pyrvinium pamoate.
Conclusion: Our study suggests that the UBE3C–LRP5 fusion is a promising therapeutic target for head and neck cancer and that pyrvinium pamoate may be a potential drug candidate for treating head and neck cancer harboring this fusion.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India