MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Abstract CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in blad...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45796-w |
| _version_ | 1797274061691158528 |
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| author | Jian Ma Lei Li Bohan Ma Tianjie Liu Zixi Wang Qi Ye Yunhua Peng Bin Wang Yule Chen Shan Xu Ke Wang Fabin Dang Xinyang Wang Zixuan Zeng Yanlin Jian Zhihua Ren Yizeng Fan Xudong Li Jing Liu Yang Gao Wenyi Wei Lei Li |
| author_facet | Jian Ma Lei Li Bohan Ma Tianjie Liu Zixi Wang Qi Ye Yunhua Peng Bin Wang Yule Chen Shan Xu Ke Wang Fabin Dang Xinyang Wang Zixuan Zeng Yanlin Jian Zhihua Ren Yizeng Fan Xudong Li Jing Liu Yang Gao Wenyi Wei Lei Li |
| author_sort | Jian Ma |
| collection | DOAJ |
| description | Abstract CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i. |
| first_indexed | 2024-03-07T14:52:59Z |
| format | Article |
| id | doaj.art-dccbb5c89d334e1bb8402b77a3adea66 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:59Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-dccbb5c89d334e1bb8402b77a3adea662024-03-05T19:37:01ZengNature PortfolioNature Communications2041-17232024-02-0115111610.1038/s41467-024-45796-wMYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradationJian Ma0Lei Li1Bohan Ma2Tianjie Liu3Zixi Wang4Qi Ye5Yunhua Peng6Bin Wang7Yule Chen8Shan Xu9Ke Wang10Fabin Dang11Xinyang Wang12Zixuan Zeng13Yanlin Jian14Zhihua Ren15Yizeng Fan16Xudong Li17Jing Liu18Yang Gao19Wenyi Wei20Lei Li21Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityCenter for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityKintor Parmaceutical, IncDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.https://doi.org/10.1038/s41467-024-45796-w |
| spellingShingle | Jian Ma Lei Li Bohan Ma Tianjie Liu Zixi Wang Qi Ye Yunhua Peng Bin Wang Yule Chen Shan Xu Ke Wang Fabin Dang Xinyang Wang Zixuan Zeng Yanlin Jian Zhihua Ren Yizeng Fan Xudong Li Jing Liu Yang Gao Wenyi Wei Lei Li MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation Nature Communications |
| title | MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation |
| title_full | MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation |
| title_fullStr | MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation |
| title_full_unstemmed | MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation |
| title_short | MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation |
| title_sort | myc induces cdk4 6 inhibitors resistance by promoting prb1 degradation |
| url | https://doi.org/10.1038/s41467-024-45796-w |
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