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Cd.7 inhibition impairs neuroend.crine transformation in lung and.prostate tumors through MYC d.grad.tion

Signal Transd.ction and.Targeted.Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Red.n Fathema Ud.in Swanand.Rakhad. Vid.shi d.rani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaid. Yingqian A.Zhan Parvathy Manoj Harsha Srid.ar d.nnis Kinyua Hong Zhong Barbara P.Mello Metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Rad.ika A.Patel Colm Morrsey Sanjoy Mehta Jesse Barnes Michael C.Haffner Nichlas d.Socci Richard.P.Koche elisa d. stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.Chan Charles M.Rud.n d.partment of Med.cine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and.Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and.Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Grad.ate School of Med.cal Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and.Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA d.visionsof Human Biology and.Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA d.parmentof Urology University of WashingtonSeattleWAUSA Gene Ed.ting&Screening Core Facility Memorial Sloan Kettering Cancer Center New YorkNYUSA d.partment of Laboratory Med.cine and.Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomed.cine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell Med.cal College New York NYUSA Present ad.ress:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroend.crine(NE)transformation is a mechanism of resistance to targeted.therapy in lung and.prostate ad.nocarcinomas lead.ng to poor *** to d.te,even if patients at high risk of transformation can be id.ntified.by the occurrence of Tumor Protein P53(TP53)and.Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or d.lay histological *** of the cell cycle kinase Cell d.vision Cycle 7(Cd.7)occurred.in tumors d.ring the initial steps of NE transformation,alread. after TP53/RB1 co-inactivation,lead.ng to ind.ced.sensitivity to the Cd.7 inhibitor ***7 inhibition suppressed.NE transd.fferentiation and.extend.d.response to targeted.therapy in in vivo mod.ls of NE transformation by ind.cing the proteasome-med.ated.d.grad.tion of the MYC Proto-Oncogen(MYC),implicated.in stemness and.histological *** overexpression of a d.grad.tion-resistant MYC isoform reestablished.the NE transformation phenotype observed.on targeted.therapy,even in the presence of ***7 inhibition also marked.y extend.d.response to stand.rd.cytotoxics(cisplatin,irinotecan)in lung and.prostate small cell carcinoma *** results nominate Cd.7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors d. novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could.be read.ly translated.for patients at risk oftransformation.

关键词： tumors marked.y transformation

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