CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation.

Autor: Quintanal-Villalonga A; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. alvacot@hotmail.com., Kawasaki K; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Redin E; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Uddin F; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rakhade S; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA., Durani V; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Sabet A; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Shafer M; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Karthaus WR; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, Switzerland., Zaidi S; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Zhan YA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Manoj P; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sridhar H; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kinyua D; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Zhong H; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Mello BP; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Ciampricotti M; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Bhanot UK; Pathology Core Facility, Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, USA., Linkov I; Pathology Core Facility, Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, USA., Qiu J; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Patel RA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA., Morrissey C; Department of Urology, University of Washington, Seattle, WA, USA., Mehta S; Gene Editing & Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Barnes J; Gene Editing & Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Haffner MC; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Socci ND; Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Koche RP; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., de Stanchina E; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Molina-Pinelo S; Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, Seville, Spain., Salehi S; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yu HA; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medical College, New York, NY, USA., Chan JM; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rudin CM; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudinc@mskcc.org.; Weill Cornell Medical College, New York, NY, USA. rudinc@mskcc.org.
Jazyk: angličtina
Zdroj: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2024 Jul 26; Vol. 9 (1), pp. 189. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1038/s41392-024-01908-y
Abstrakt: Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified 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 delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: