Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer
Abstract Background Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurr...
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BMC
2025-01-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-024-00590-8 |
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| author | Sharon Pei Yi Chan Celestia Pei Xuan Yeo Boon Hao Hong Evelyn Mui Cheng Tan Chaw Yee Beh Eugenia Li Ling Yeo Dennis Jun Jie Poon Pek Lim Chu Khee Chee Soo Melvin Lee Kiang Chua Edward Kai-Hua Chow |
| author_facet | Sharon Pei Yi Chan Celestia Pei Xuan Yeo Boon Hao Hong Evelyn Mui Cheng Tan Chaw Yee Beh Eugenia Li Ling Yeo Dennis Jun Jie Poon Pek Lim Chu Khee Chee Soo Melvin Lee Kiang Chua Edward Kai-Hua Chow |
| author_sort | Sharon Pei Yi Chan |
| collection | DOAJ |
| description | Abstract Background Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance. In this study, we utilized a combinatorial functionomics approach, the Quadratic Phenotypic Optimization Platform (QPOP), to rationally design drug pairings that exploit the molecular fingerprint and vulnerability of established in vitro isogenic radioresistant (RR)-HNC models. Methods A QPOP-specific protocol was applied to RR-HNC models to rank and compare all possible drug combinations from a 12-drug set comprising standard chemotherapy, small molecule inhibitors and targeted therapies specific to HNC. Drug combination efficacy was evaluated by computing combination index scores, and by measuring apoptotic response. Drug targeting was validated by western blot analyses, and the Comet assay was used to quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) efficacy in RR models was further examined by in vivo studies, and genetic and chemical inhibition of major Class I/II HDACs. Regulatory roles of HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift and ChIP-qPCR assays. Comparative transcriptomic analyses were employed to determine the prognostic significance of targeting HDAC6. Results We report the therapeutic potential of combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) to re-sensitize RR-HNC cells and showed increased DNA damage underlying enhanced synergy. We further refined this RR-specific drug combination and prioritized HDAC6 as a targetable dependency in reversing radioresistance. We provide mechanistic insights into HDAC6-mediated regulation via a crosstalk involving SP1 and oncogenic and repair genes. From two independent patient cohorts, we identified a four-gene signature that may have discriminative ability to predict for radioresistance and amenable to HDAC6 inhibition. Conclusion We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC. |
| format | Article |
| id | doaj-art-a0d365f982b84ddebba9a121e4b36186 |
| institution | Kabale University |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Experimental Hematology & Oncology |
| spelling | doaj-art-a0d365f982b84ddebba9a121e4b361862025-01-19T12:13:01ZengBMCExperimental Hematology & Oncology2162-36192025-01-0114112210.1186/s40164-024-00590-8Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancerSharon Pei Yi Chan0Celestia Pei Xuan Yeo1Boon Hao Hong2Evelyn Mui Cheng Tan3Chaw Yee Beh4Eugenia Li Ling Yeo5Dennis Jun Jie Poon6Pek Lim Chu7Khee Chee Soo8Melvin Lee Kiang Chua9Edward Kai-Hua Chow10Cancer Science Institute of Singapore, National University of SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeDivision of Medical Sciences, National Cancer Centre SingaporeCancer Science Institute of Singapore, National University of SingaporeAbstract Background Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance. In this study, we utilized a combinatorial functionomics approach, the Quadratic Phenotypic Optimization Platform (QPOP), to rationally design drug pairings that exploit the molecular fingerprint and vulnerability of established in vitro isogenic radioresistant (RR)-HNC models. Methods A QPOP-specific protocol was applied to RR-HNC models to rank and compare all possible drug combinations from a 12-drug set comprising standard chemotherapy, small molecule inhibitors and targeted therapies specific to HNC. Drug combination efficacy was evaluated by computing combination index scores, and by measuring apoptotic response. Drug targeting was validated by western blot analyses, and the Comet assay was used to quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) efficacy in RR models was further examined by in vivo studies, and genetic and chemical inhibition of major Class I/II HDACs. Regulatory roles of HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift and ChIP-qPCR assays. Comparative transcriptomic analyses were employed to determine the prognostic significance of targeting HDAC6. Results We report the therapeutic potential of combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) to re-sensitize RR-HNC cells and showed increased DNA damage underlying enhanced synergy. We further refined this RR-specific drug combination and prioritized HDAC6 as a targetable dependency in reversing radioresistance. We provide mechanistic insights into HDAC6-mediated regulation via a crosstalk involving SP1 and oncogenic and repair genes. From two independent patient cohorts, we identified a four-gene signature that may have discriminative ability to predict for radioresistance and amenable to HDAC6 inhibition. Conclusion We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC.https://doi.org/10.1186/s40164-024-00590-8Head and neck cancerRadioresistanceCombination therapyHDAC6 inhibition |
| spellingShingle | Sharon Pei Yi Chan Celestia Pei Xuan Yeo Boon Hao Hong Evelyn Mui Cheng Tan Chaw Yee Beh Eugenia Li Ling Yeo Dennis Jun Jie Poon Pek Lim Chu Khee Chee Soo Melvin Lee Kiang Chua Edward Kai-Hua Chow Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer Experimental Hematology & Oncology Head and neck cancer Radioresistance Combination therapy HDAC6 inhibition |
| title | Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer |
| title_full | Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer |
| title_fullStr | Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer |
| title_full_unstemmed | Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer |
| title_short | Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer |
| title_sort | combinatorial functionomics identifies hdac6 dependent molecular vulnerability of radioresistant head and neck cancer |
| topic | Head and neck cancer Radioresistance Combination therapy HDAC6 inhibition |
| url | https://doi.org/10.1186/s40164-024-00590-8 |
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