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

被引：7

作者：

Dmello, Crismita ^{[1
]}

Sonabend, Aaron ^{[2
]}

Arrieta, Victor A. ^{[1
,3
]}

Zhang, Daniel Y. ^{[1
]}

Kanojia, Deepak ^{[1
]}

Chen, Li ^{[1
]}

Gould, Andrew ^{[1
]}

Zhang, Jiangshan ^{[2
]}

Kang, Seong Jae ^{[1
]}

Winter, Jan ^{[4
]}

Horbinski, Craig ^{[5
]}

Amidei, Christina ^{[1
]}

Gyorffy, Balazs ^{[6
,7
]}

Cordero, Alex ^{[1
]}

Chang, Catalina Lee ^{[1
]}

Castro, Brandyn ^{[1
,8
]}

Hsu, Patrick ^{[9
,10
,11
]}

Ahmed, Atique U. ^{[1
]}

Lesniak, Maciej S. ^{[1
]}

Stupp, Roger ^{[1
,12
]}

Sonabend, Adam M. ^{[1
]}

机构：

[1] Northwestern Univ, Northwestern Med Lou & Jean Malnati Brain Tumor I, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med,Dept Neurol Surg, Chicago, IL USA

[2] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[3] Univ Nacl Autonoma Mexico, Fac Med, PECEM, Mexico City, DF, Mexico

[4] German Ctr Canc Res, Funct Genom & Signaling, Heidelberg, Germany

[5] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL USA

[6] Semmelweis Univ, Dept Bioinformat, Budapest, Hungary

[7] TTK Momentum Canc Biomarker Res Grp, Budapest, Hungary

[8] Univ Chicago Med, Sect Neurol Surg, Chicago, IL USA

[9] Univ Calif Berkeley, Innovat Genom Inst, Berkeley, CA USA

[10] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA USA

[11] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA USA

[12] Northwestern Univ, Feinberg Sch Med, Dept Neurol & Oncol, Chicago, IL USA

来源：

CLINICAL CANCER RESEARCH | 2022年 / 28卷 / 14期

关键词：

III RANDOMIZED-TRIAL; NEOADJUVANT PACLITAXEL; OVARIAN-CANCER; SENSITIVITY; CHEMOTHERAPY; SURVIVAL; APOPTOSIS; DELIVERY; COMPLEX; GENOME;

D O I：

10.1158/1078-0432.CCR-21-2563

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Paclitaxel (PTX) is one of the most potent and com-monly 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 progres-sion-free survival. Results: Combination of CRISPR screen results with out-comes 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 IRE1z. Conclusions: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.

引用

页码：3156 / 3169

页数：14

共 51 条

[1] The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1 [J].