An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma
The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13497 |
| _version_ | 1797467835148009472 |
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| author | Markus Bredel Hyunsoo Kim James A. Bonner |
| author_facet | Markus Bredel Hyunsoo Kim James A. Bonner |
| author_sort | Markus Bredel |
| collection | DOAJ |
| description | The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy in ErbB-driven head and neck squamous cell carcinoma. We here present a cohort-based; genome-wide analysis of 488 head and neck squamous cell carcinomas curated as part of The Cancer Genome Atlas Project to characterize genes that are significantly positively co-regulated with the four ErbB proteins and those that are shared among all ErbBs denoting a common ErbB co-regulon. Significant positive gene correlations involved hundreds of genes that were co-expressed with the four ErbB family members (<i>q</i> < 0.05). A common; overlapping co-regulon consisted of a core set of 268 genes that were uniformly co-regulated with all four ErbB genes and highly enriched for functions in chromatin organization and histone modifications. This high-priority set of genes contained ten putative antineoplastic drug-gene interactions. The nature and directionality of these ten drug-gene associations was an inhibiting interaction for seven (PIK3CB; PIK3C2B; HDAC4; FRK; PRKCE; EPHA4; and DYRK1A) of them in which the drug decreases the biological activity or expression of the gene target. For three (CHD4; ARID1A; and PBRM1) of the associations; the directionality of the interaction was such that the gene predicted sensitivit y to the drug suggesting utility as potential response biomarkers. Drug-gene interactions that predicted the gene product to be reduced by the drug included a variety of potential targeted molecular agent classes. This unbiased genome-wide analysis identified a target-rich environment for multimodal therapeutic approaches in tumors that are putatively ErbB-driven. The results of this study require preclinical validation before ultimately devising lines of combinatorial treatment strategies for ErbB-dependent head and neck squamous cell carcinomas that incorporate these findings. |
| first_indexed | 2024-03-09T18:59:21Z |
| format | Article |
| id | doaj.art-269127da239d44ecb9d8073ed7376eed |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:59:21Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-269127da239d44ecb9d8073ed7376eed2023-11-24T05:08:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123211349710.3390/ijms232113497An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell CarcinomaMarkus Bredel0Hyunsoo Kim1James A. Bonner2Department of Radiation Oncology, O’Neal Comprehensive Cancer Center, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USALineberger Comprehensive Cancer Center, University of Northern Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Radiation Oncology, O’Neal Comprehensive Cancer Center, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USAThe ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy in ErbB-driven head and neck squamous cell carcinoma. We here present a cohort-based; genome-wide analysis of 488 head and neck squamous cell carcinomas curated as part of The Cancer Genome Atlas Project to characterize genes that are significantly positively co-regulated with the four ErbB proteins and those that are shared among all ErbBs denoting a common ErbB co-regulon. Significant positive gene correlations involved hundreds of genes that were co-expressed with the four ErbB family members (<i>q</i> < 0.05). A common; overlapping co-regulon consisted of a core set of 268 genes that were uniformly co-regulated with all four ErbB genes and highly enriched for functions in chromatin organization and histone modifications. This high-priority set of genes contained ten putative antineoplastic drug-gene interactions. The nature and directionality of these ten drug-gene associations was an inhibiting interaction for seven (PIK3CB; PIK3C2B; HDAC4; FRK; PRKCE; EPHA4; and DYRK1A) of them in which the drug decreases the biological activity or expression of the gene target. For three (CHD4; ARID1A; and PBRM1) of the associations; the directionality of the interaction was such that the gene predicted sensitivit y to the drug suggesting utility as potential response biomarkers. Drug-gene interactions that predicted the gene product to be reduced by the drug included a variety of potential targeted molecular agent classes. This unbiased genome-wide analysis identified a target-rich environment for multimodal therapeutic approaches in tumors that are putatively ErbB-driven. The results of this study require preclinical validation before ultimately devising lines of combinatorial treatment strategies for ErbB-dependent head and neck squamous cell carcinomas that incorporate these findings.https://www.mdpi.com/1422-0067/23/21/13497glioblastomaErbBregulonmultimodal precision therapyco-druggable targetshead and neck squamous cell carcinoma |
| spellingShingle | Markus Bredel Hyunsoo Kim James A. Bonner An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma International Journal of Molecular Sciences glioblastoma ErbB regulon multimodal precision therapy co-druggable targets head and neck squamous cell carcinoma |
| title | An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma |
| title_full | An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma |
| title_fullStr | An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma |
| title_full_unstemmed | An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma |
| title_short | An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma |
| title_sort | erbb lineage co regulon harbors potentially co druggable targets for multimodal precision therapy in head and neck squamous cell carcinoma |
| topic | glioblastoma ErbB regulon multimodal precision therapy co-druggable targets head and neck squamous cell carcinoma |
| url | https://www.mdpi.com/1422-0067/23/21/13497 |
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