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

Crismita Dmello, Aarón Sonabend, Victor A. Arrieta, Daniel Y. Zhang, Deepak Kanojia, Li Chen, Andrew Gould, Jiangshan Zhang, Seong Jae Kang, Jan Winter, Craig Horbinski, Christina Amidei, Balázs Győrffy, Alex Cordero, Catalina Lee Chang, Brandyn Castro, Patrick Hsu, Atique U. Ahmed, Maciej S. Lesniak, Roger StuppAdam M. Sonabend*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 IRE1a. Conclusions: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.

Original languageEnglish (US)
Pages (from-to)3156-3169
Number of pages14
JournalClinical Cancer Research
Volume28
Issue number14
DOIs
StatePublished - Jul 15 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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