{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:23:09Z","timestamp":1793330589575,"version":"4.5.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81925028"],"award-info":[{"award-number":["81925028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82230097"],"award-info":[{"award-number":["82230097"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173037"],"award-info":[{"award-number":["82173037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273106"],"award-info":[{"award-number":["82273106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1038\/s41467-024-45796-w","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T13:02:51Z","timestamp":1709211771000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["MYC induces CDK4\/6 inhibitors resistance by promoting pRB1 degradation"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-4689","authenticated-orcid":false,"given":"Jian","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-8263","authenticated-orcid":false,"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2321-1869","authenticated-orcid":false,"given":"Tianjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8814-2801","authenticated-orcid":false,"given":"Yunhua","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yule","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1954-8231","authenticated-orcid":false,"given":"Fabin","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizeng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3113-4015","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4928-8722","authenticated-orcid":false,"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"45796_CR1","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.ccell.2020.03.010","volume":"37","author":"M Alvarez-Fernandez","year":"2020","unstructured":"Alvarez-Fernandez, M. & Malumbres, M. Mechanisms of sensitivity and resistance to CDK4\/6 inhibition. Cancer Cell 37, 514\u2013529 (2020).","journal-title":"Cancer Cell"},{"key":"45796_CR2","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/nature23465","volume":"548","author":"S Goel","year":"2017","unstructured":"Goel, S. et al. CDK4\/6 inhibition triggers anti-tumour immunity. Nature 548, 471\u2013475 (2017).","journal-title":"Nature"},{"key":"45796_CR3","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1158\/2159-8290.CD-16-0095","volume":"6","author":"A Patnaik","year":"2016","unstructured":"Patnaik, A. et al. Efficacy and safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 6, 740\u2013753 (2016).","journal-title":"Cancer Discov."},{"key":"45796_CR4","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1056\/NEJMoa1607303","volume":"375","author":"RS Finn","year":"2016","unstructured":"Finn, R. S. et al. Palbociclib and Letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925\u20131936 (2016).","journal-title":"N. Engl. J. Med."},{"key":"45796_CR5","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1038\/onc.2016.379","volume":"36","author":"C Yang","year":"2017","unstructured":"Yang, C. et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4\/6 inhibitors and loss of ER signaling and dependence. Oncogene 36, 2255\u20132264 (2017).","journal-title":"Oncogene"},{"key":"45796_CR6","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1158\/0008-5472.CAN-15-0728","volume":"76","author":"MT Herrera-Abreu","year":"2016","unstructured":"Herrera-Abreu, M. T. et al. Early adaptation and acquired resistance to CDK4\/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 76, 2301\u20132313 (2016).","journal-title":"Cancer Res."},{"key":"45796_CR7","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1158\/2159-8290.CD-19-1390","volume":"10","author":"SA Wander","year":"2020","unstructured":"Wander, S. A. et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4\/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 10, 1174\u20131193 (2020).","journal-title":"Cancer Discov."},{"key":"45796_CR8","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1093\/annonc\/mdx784","volume":"29","author":"R Condorelli","year":"2018","unstructured":"Condorelli, R. et al. Polyclonal RB1 mutations and acquired resistance to CDK 4\/6 inhibitors in patients with metastatic breast cancer. Ann. Oncol. 29, 640\u2013645 (2018).","journal-title":"Ann. Oncol."},{"key":"45796_CR9","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1158\/2159-8290.CD-18-0264","volume":"8","author":"B O\u2019Leary","year":"2018","unstructured":"O\u2019Leary, B. et al. The genetic landscape and clonal evolution of breast cancer resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov. 8, 1390\u20131403 (2018).","journal-title":"Cancer Discov."},{"key":"45796_CR10","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrclinonc.2016.26","volume":"13","author":"B O\u2019Leary","year":"2016","unstructured":"O\u2019Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4\/6 inhibitors. Nat. Rev. Clin. Oncol. 13, 417\u2013430 (2016).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"45796_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25700-6","volume":"12","author":"F Dang","year":"2021","unstructured":"Dang, F. et al. Inhibition of CK1\u03b5 potentiates the therapeutic efficacy of CDK4\/6 inhibitor in breast cancer. Nat. Commun. 12, 5386 (2021).","journal-title":"Nat. Commun."},{"key":"45796_CR12","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1002\/ijc.32020","volume":"145","author":"K Pandey","year":"2019","unstructured":"Pandey, K. et al. Molecular mechanisms of resistance to CDK4\/6 inhibitors in breast cancer: A review. Int. J. Cancer 145, 1179\u20131188 (2019).","journal-title":"Int. J. Cancer"},{"key":"45796_CR13","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1016\/j.ccell.2021.08.009","volume":"39","author":"K Freeman-Cook","year":"2021","unstructured":"Freeman-Cook, K. et al. Expanding control of the tumor cell cycle with a CDK2\/4\/6 inhibitor. Cancer Cell 39, 1404\u20131421.e1411 (2021).","journal-title":"Cancer Cell"},{"key":"45796_CR14","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.ccell.2018.11.006","volume":"34","author":"Z Li","year":"2018","unstructured":"Li, Z. et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4\/6 inhibitors via the Hippo pathway. Cancer Cell 34, 893\u2013905.e898 (2018).","journal-title":"Cancer Cell"},{"key":"45796_CR15","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/358259a0","volume":"358","author":"SJ Weintraub","year":"1992","unstructured":"Weintraub, S. J., Prater, C. A. & Dean, D. C. Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358, 259\u2013261 (1992).","journal-title":"Nature"},{"key":"45796_CR16","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/375812a0","volume":"375","author":"SJ Weintraub","year":"1995","unstructured":"Weintraub, S. J. et al. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature 375, 812\u2013815 (1995).","journal-title":"Nature"},{"key":"45796_CR17","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nrc2399","volume":"8","author":"DL Burkhart","year":"2008","unstructured":"Burkhart, D. L. & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat. Rev. Cancer 8, 671\u2013682 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"45796_CR18","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.molcel.2018.10.034","volume":"73","author":"X Jin","year":"2019","unstructured":"Jin, X. et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-\u03baB activation and PD-L1 expression. Mol. Cell 73, 22\u201335.e26 (2019).","journal-title":"Mol. Cell"},{"key":"45796_CR19","doi-asserted-by":"publisher","first-page":"e02872","DOI":"10.7554\/eLife.02872","volume":"3","author":"AM Narasimha","year":"2014","unstructured":"Narasimha, A. M. et al. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife 3, e02872 (2014).","journal-title":"Elife"},{"key":"45796_CR20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1001\/jamaoncol.2015.4701","volume":"2","author":"AS Clark","year":"2016","unstructured":"Clark, A. S. et al. Palbociclib (PD0332991)-a selective and potent cyclin-dependent kinase inhibitor: a review of pharmacodynamics and clinical development. JAMA Oncol. 2, 253\u2013260 (2016).","journal-title":"JAMA Oncol."},{"key":"45796_CR21","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1126\/science.2537532","volume":"243","author":"N Dyson","year":"1989","unstructured":"Dyson, N., Howley, P. M., M\u00fcnger, K. & Harlow, E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934\u2013937 (1989).","journal-title":"Science"},{"key":"45796_CR22","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/nrm3567","volume":"14","author":"FA Dick","year":"2013","unstructured":"Dick, F. A. & Rubin, S. M. Molecular mechanisms underlying RB protein function. Nat. Rev. Mol. Cell Biol. 14, 297\u2013306 (2013).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"45796_CR23","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/s41586-019-1056-z","volume":"569","author":"F Bertucci","year":"2019","unstructured":"Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560\u2013564 (2019).","journal-title":"Nature"},{"key":"45796_CR24","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1126\/science.aah4199","volume":"355","author":"SY Ku","year":"2017","unstructured":"Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78\u201383 (2017).","journal-title":"Science"},{"key":"45796_CR25","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1172\/JCI132031","volume":"130","author":"J Mateo","year":"2020","unstructured":"Mateo, J. et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J. Clin. Investig. 130, 1743\u20131751 (2020).","journal-title":"J. Clin. Investig."},{"key":"45796_CR26","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.cell.2012.03.003","volume":"149","author":"CV Dang","year":"2012","unstructured":"Dang, C. V. MYC on the path to cancer. Cell 149, 22\u201335 (2012).","journal-title":"Cell"},{"key":"45796_CR27","doi-asserted-by":"publisher","first-page":"5164","DOI":"10.1158\/0008-5472.CAN-10-4633","volume":"71","author":"N Palaskas","year":"2011","unstructured":"Palaskas, N. et al. 18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers. Cancer Res. 71, 5164\u20135174 (2011).","journal-title":"Cancer Res."},{"key":"45796_CR28","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1126\/science.1071489","volume":"297","author":"M Jain","year":"2002","unstructured":"Jain, M. et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102\u2013104 (2002).","journal-title":"Science"},{"key":"45796_CR29","doi-asserted-by":"publisher","first-page":"4471","DOI":"10.1158\/0008-5472.CAN-05-1172","volume":"65","author":"CM Shachaf","year":"2005","unstructured":"Shachaf, C. M. & Felsher, D. W. Tumor dormancy and MYC inactivation: pushing cancer to the brink of normalcy. Cancer Res. 65, 4471\u20134474 (2005).","journal-title":"Cancer Res."},{"key":"45796_CR30","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.molcel.2021.11.016","volume":"82","author":"SK Das","year":"2022","unstructured":"Das, S. K. et al. MYC assembles and stimulates topoisomerases 1 and 2 in a \u201ctopoisome. Mol. Cell 82, 140\u2013158 e112 (2022).","journal-title":"Mol. Cell"},{"key":"45796_CR31","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1158\/2159-8290.CD-15-0507","volume":"5","author":"ZE Stine","year":"2015","unstructured":"Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC, metabolism, and cancer. Cancer Discov. 5, 1024\u20131039 (2015).","journal-title":"Cancer Discov."},{"key":"45796_CR32","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1038\/nrc2231","volume":"8","author":"N Meyer","year":"2008","unstructured":"Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976\u2013990 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"45796_CR33","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/s41580-020-0215-2","volume":"21","author":"A Baluapuri","year":"2020","unstructured":"Baluapuri, A., Wolf, E. & Eilers, M. Target gene-independent functions of MYC oncoproteins. Nat. Rev. Mol. Cell Biol. 21, 255\u2013267 (2020).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"45796_CR34","doi-asserted-by":"publisher","first-page":"103756","DOI":"10.1016\/j.ebiom.2021.103756","volume":"75","author":"V Llombart","year":"2022","unstructured":"Llombart, V. & Mansour, M. R. Therapeutic targeting of \u201cundruggable\u201d MYC. EBioMedicine 75, 103756 (2022).","journal-title":"EBioMedicine"},{"key":"45796_CR35","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41392-018-0008-7","volume":"3","author":"H Chen","year":"2018","unstructured":"Chen, H., Liu, H. & Qing, G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct. Target Ther. 3, 5 (2018).","journal-title":"Signal Transduct. Target Ther."},{"key":"45796_CR36","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.cell.2012.07.023","volume":"150","author":"D Nijhawan","year":"2012","unstructured":"Nijhawan, D. et al. Cancer vulnerabilities unveiled by genomic loss. Cell 150, 842\u2013854 (2012).","journal-title":"Cell"},{"key":"45796_CR37","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature11331","volume":"488","author":"FL Muller","year":"2012","unstructured":"Muller, F. L. et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337\u2013342 (2012).","journal-title":"Nature"},{"key":"45796_CR38","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nature21357","volume":"542","author":"D Zhao","year":"2017","unstructured":"Zhao, D. et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484\u2013488 (2017).","journal-title":"Nature"},{"key":"45796_CR39","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.ccell.2018.08.008","volume":"34","author":"P Razavi","year":"2018","unstructured":"Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427\u2013438.e426 (2018).","journal-title":"Cancer Cell"},{"key":"45796_CR40","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature12965","volume":"507","author":"Cancer Genome Atlas Research, N.","year":"2014","unstructured":"Cancer Genome Atlas Research, N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315\u2013322 (2014).","journal-title":"Nature"},{"key":"45796_CR41","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.cell.2015.05.001","volume":"161","author":"D Robinson","year":"2015","unstructured":"Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215\u20131228 (2015).","journal-title":"Cell"},{"key":"45796_CR42","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nature11412","volume":"490","author":"Cancer Genome Atlas, N.","year":"2012","unstructured":"Cancer Genome Atlas, N. Comprehensive molecular portraits of human breast tumours. Nature 490, 61\u201370 (2012).","journal-title":"Nature"},{"key":"45796_CR43","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nature03677","volume":"435","author":"KA O\u2019Donnell","year":"2005","unstructured":"O\u2019Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839\u2013843 (2005).","journal-title":"Nature"},{"key":"45796_CR44","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1002\/1097-0215(20000915)87:6<787::AID-IJC4>3.0.CO;2-6","volume":"87","author":"A Pajic","year":"2000","unstructured":"Pajic, A. et al. Cell cycle activation by c-myc in a burkitt lymphoma model cell line. Int J. Cancer 87, 787\u2013793 (2000).","journal-title":"Int J. Cancer"},{"key":"45796_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25700-6","volume":"12","author":"F Dang","year":"2021","unstructured":"Dang, F. et al. Inhibition of CK1epsilon potentiates the therapeutic efficacy of CDK4\/6 inhibitor in breast cancer. Nat. Commun. 12, 5386 (2021).","journal-title":"Nat. Commun."},{"key":"45796_CR46","doi-asserted-by":"publisher","first-page":"4171","DOI":"10.1074\/jbc.AC119.012066","volume":"295","author":"TB Lear","year":"2020","unstructured":"Lear, T. B. et al. Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis. J. Biol. Chem. 295, 4171\u20134180 (2020).","journal-title":"J. Biol. Chem."},{"key":"45796_CR47","doi-asserted-by":"publisher","first-page":"11663","DOI":"10.1074\/jbc.M809374200","volume":"284","author":"CM Cummings","year":"2009","unstructured":"Cummings, C. M., Bentley, C. A., Perdue, S. A., Baas, P. W. & Singer, J. D. The Cul3\/Klhdc5 E3 ligase regulates p60\/katanin and is required for normal mitosis in mammalian cells. J. Biol. Chem. 284, 11663\u201311675 (2009).","journal-title":"J. Biol. Chem."},{"key":"45796_CR48","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrm1547","volume":"6","author":"MD Petroski","year":"2005","unstructured":"Petroski, M. D. & Deshaies, R. J. Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 6, 9\u201320 (2005).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"45796_CR49","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.molcel.2018.10.034","volume":"73","author":"X Jin","year":"2019","unstructured":"Jin, X. et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol. Cell 73, 22\u201335 e26 (2019).","journal-title":"Mol. Cell"},{"key":"45796_CR50","doi-asserted-by":"publisher","first-page":"105616","DOI":"10.1016\/j.phrs.2021.105616","volume":"169","author":"S Xiang","year":"2021","unstructured":"Xiang, S. et al. Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy. Pharmacol. Res. 169, 105616 (2021).","journal-title":"Pharmacol. Res."},{"key":"45796_CR51","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-7-13","volume":"7","author":"BS Dhanoa","year":"2013","unstructured":"Dhanoa, B. S., Cogliati, T., Satish, A. G., Bruford, E. A. & Friedman, J. S. Update on the Kelch-like (KLHL) gene family. Hum. Genom. 7, 13 (2013).","journal-title":"Hum. Genom."},{"key":"45796_CR52","doi-asserted-by":"publisher","first-page":"7803","DOI":"10.1074\/jbc.M112.437996","volume":"288","author":"P Canning","year":"2013","unstructured":"Canning, P. et al. Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J. Biol. Chem. 288, 7803\u20137814 (2013).","journal-title":"J. Biol. Chem."},{"key":"45796_CR53","doi-asserted-by":"publisher","first-page":"e2003268","DOI":"10.1371\/journal.pbio.2003268","volume":"15","author":"S Gookin","year":"2017","unstructured":"Gookin, S. et al. A map of protein dynamics during cell-cycle progression and cell-cycle exit. PLoS Biol. 15, e2003268 (2017).","journal-title":"PLoS Biol."},{"key":"45796_CR54","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1126\/science.aaz6213","volume":"369","author":"E Zatulovskiy","year":"2020","unstructured":"Zatulovskiy, E., Zhang, S., Berenson, D. F., Topacio, B. R. & Skotheim, J. M. Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division. Science 369, 466\u2013471 (2020).","journal-title":"Science"},{"key":"45796_CR55","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.cell.2012.08.026","volume":"151","author":"CY Lin","year":"2012","unstructured":"Lin, C. Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56\u201367 (2012).","journal-title":"Cell"},{"key":"45796_CR56","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.cell.2018.09.027","volume":"175","author":"K Liang","year":"2018","unstructured":"Liang, K. et al. Targeting processive transcription elongation via SEC disruption for MYC-induced cancer therapy. Cell 175, 766\u2013779 e717 (2018).","journal-title":"Cell"},{"key":"45796_CR57","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1038\/s41418-022-00960-x","volume":"29","author":"Y Peng","year":"2022","unstructured":"Peng, Y. et al. Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc. Cell Death Differ. 29, 1730\u20131743 (2022).","journal-title":"Cell Death Differ."},{"key":"45796_CR58","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nature18611","volume":"535","author":"ME Matyskiela","year":"2016","unstructured":"Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature 535, 252\u2013257 (2016).","journal-title":"Nature"},{"key":"45796_CR59","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nature13527","volume":"512","author":"ES Fischer","year":"2014","unstructured":"Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49\u201353 (2014).","journal-title":"Nature"},{"key":"45796_CR60","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou, T. C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res, 70, 440\u2013446 (2010).","journal-title":"Cancer Res,"},{"key":"45796_CR61","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/s41568-018-0008-5","volume":"18","author":"FA Dick","year":"2018","unstructured":"Dick, F. A., Goodrich, D. W., Sage, J. & Dyson, N. J. Non-canonical functions of the RB protein in cancer. Nat. Rev. Cancer 18, 442\u2013451 (2018).","journal-title":"Nat. Rev. Cancer"},{"key":"45796_CR62","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1101\/gad.282145.116","volume":"30","author":"NJ Dyson","year":"2016","unstructured":"Dyson, N. J. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 30, 1492\u20131502 (2016).","journal-title":"Genes Dev."},{"key":"45796_CR63","doi-asserted-by":"publisher","first-page":"e202103090","DOI":"10.1083\/jcb.202103090","volume":"220","author":"JR Whitfield","year":"2021","unstructured":"Whitfield, J. R. & Soucek, L. The long journey to bring a Myc inhibitor to the clinic. J. Cell Biol. 220, e202103090 (2021).","journal-title":"J. Cell Biol."},{"key":"45796_CR64","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.ccell.2019.10.001","volume":"36","author":"H Han","year":"2019","unstructured":"Han, H. et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell 36, 483\u2013497 e415 (2019).","journal-title":"Cancer Cell"},{"key":"45796_CR65","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1021\/jm801278g","volume":"52","author":"G Mustata","year":"2009","unstructured":"Mustata, G. et al. Discovery of novel Myc-Max heterodimer disruptors with a three-dimensional pharmacophore model. J. Med Chem. 52, 1247\u20131250 (2009).","journal-title":"J. Med Chem."},{"key":"45796_CR66","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1158\/2159-8290.CD-14-1040","volume":"5","author":"A Wiegering","year":"2015","unstructured":"Wiegering, A. et al. Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 5, 768\u2013781 (2015).","journal-title":"Cancer Discov."},{"key":"45796_CR67","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/nm1606","volume":"13","author":"A Goga","year":"2007","unstructured":"Goga, A., Yang, D., Tward, A. D., Morgan, D. O. & Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13, 820\u2013827 (2007).","journal-title":"Nat. Med."},{"key":"45796_CR68","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1038\/nm.4213","volume":"22","author":"D Horiuchi","year":"2016","unstructured":"Horiuchi, D. et al. PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat. Med. 22, 1321\u20131329 (2016).","journal-title":"Nat. Med."},{"key":"45796_CR69","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","volume":"21","author":"M Bekes","year":"2022","unstructured":"Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181\u2013200 (2022).","journal-title":"Nat. Rev. Drug Discov."},{"key":"45796_CR70","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202104344","volume":"9","author":"Y Xu","year":"2022","unstructured":"Xu, Y. et al. A selective small-molecule c-Myc Degrader potently regresses Lethal c-Myc overexpressing tumors. Adv. Sci. 9, e2104344 (2022).","journal-title":"Adv. Sci."},{"key":"45796_CR71","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1038\/s41418-022-00951-y","volume":"29","author":"Y Fan","year":"2022","unstructured":"Fan, Y. et al. ERK1\/2 inhibits Cullin 3\/SPOP-mediated PrLZ ubiquitination and degradation to modulate prostate cancer progression. Cell Death Differ. 29, 1611\u20131624 (2022).","journal-title":"Cell Death Differ."},{"key":"45796_CR72","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s40880-018-0329-5","volume":"38","author":"F Zhang","year":"2018","unstructured":"Zhang, F. et al. Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response. Cancer Commun. 38, 60 (2018).","journal-title":"Cancer Commun."},{"key":"45796_CR73","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s40880-018-0323-y","volume":"38","author":"P Zhao","year":"2018","unstructured":"Zhao, P. et al. Personalized treatment based on mini patient-derived xenografts and WES\/RNA sequencing in a patient with metastatic duodenal adenocarcinoma. Cancer Commun. 38, 54 (2018).","journal-title":"Cancer Commun."},{"key":"45796_CR74","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1006\/jmbi.1998.1914","volume":"281","author":"P Lavigne","year":"1998","unstructured":"Lavigne, P. et al. Insights into the mechanism of heterodimerization from the 1H-NMR solution structure of the c-Myc-Max heterodimeric leucine zipper. J. Mol. Biol. 281, 165\u2013181 (1998).","journal-title":"J. Mol. Biol."},{"key":"45796_CR75","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26049-6","volume":"12","author":"J Ma","year":"2021","unstructured":"Ma, J. et al. SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition. Nat. Commun. 12, 5779 (2021).","journal-title":"Nat. Commun."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45796-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45796-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45796-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T18:07:31Z","timestamp":1709230051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45796-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,29]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["45796"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-45796-w","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,29]]},"assertion":[{"value":"24 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"W.W. is a co-founder and consultant for the ReKindle Therapeutics. Z.R. is the VP of Kintor Pharmaceutical, Inc. Other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study protocol of clinical samples for bladder cancer tissue microarray slides was approved by the Institutional Ethics Committee of Shanghai Outdo Biotech Company. All patients provided written informed consent to participate in the study. The mini PDX model protocol was approved by the Institutional Ethics Committee of Shanghai LIDE Biotech.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"<!--Emphasis Type='Bold' removed-->Ethics"}}],"article-number":"1871"}}