Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma.

Autor:	Dmello C; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Sonabend A; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Arrieta VA; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.; PECEM, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico., Zhang DY; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Kanojia D; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Chen L; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Gould A; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Zhang J; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Kang SJ; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Winter J; Functional Genomics and Signaling, German Center for Cancer Research, Heidelberg, Germany., Horbinski C; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Amidei C; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Győrffy B; Department of Bioinformatics, Semmelweis University, Budapest, Hungary.; TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary., Cordero A; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Chang CL; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Castro B; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.; Section of Neurological Surgery, University of Chicago Medicine, Chicago, Illinois., Hsu P; Innovative Genomics Institute, University of California, Berkeley, California.; Department of Bioengineering, University of California, Berkeley, California.; Center for Computational Biology, University of California, Berkeley, California., Ahmed AU; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Lesniak MS; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Stupp R; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.; Department of Neurology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Sonabend AM; Department of Neurological Surgery, Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Jul 15; Vol. 28 (14), pp. 3156-3169.
DOI:	10.1158/1078-0432.CCR-21-2563
Abstrakt:	Purpose: Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy. Experimental Design: To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knockout (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival. Results: Combination of CRISPR screen results with outcomes from patients with taxane-treated breast cancer led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells, and in multiple intracranial glioma xenografts models. KO of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α. Conclusions: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu