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

Abstract

Purpose: Paclitaxel (PTX) is one 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 (GBMs). 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 knock-out (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 taxane-treated breast cancer patients 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. Knockout 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. Conclusion: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.

Preclinical multi‐physiologic monitoring of immediate‐early responses to diverse treatment strategies in breast cancer by optoacoustic imaging

“…PTX is a commonly used chemotherapy drug for a variety of cancers and interferes with cell mitosis mechanism. As a first‐line chemotherapy drug for breast cancer, it has been extensively used to treat breast cancer, especially advanced metastatic breast cancer [47–49]. In our study, we observed that tumor sO 2 first increased and then significantly decreased after PTX treatment, which may be attributed to the anti‐angiogenic effects of PTX and its potential to improve the tumor microenvironment.…”

Combining causal and correlative approaches to discover biomarkers of response to paclitaxel

“…Paclitaxel (PTX) is a widely used and highly potent chemotherapeutic agent, being the basis of regimens to treat breast, pancreatic, ovarian, and lung non-small cell lung carcinomas [ 1 ]. However, it is estimated that half of the patients treated with PTX do not receive a therapeutic benefit, yet are exposed to its toxic effects, causing physical, psychological, and social discomfort [ 2 , 3 ].…”

“…In glioblastoma (GBM) treatment, PTX has proven a high efficacy at nanomolar concentrations in achieving in vitro tumor cell death, with an IC50 1,400-fold lower than temozolomide, standard-of-care treatment [ 2 – 4 ]. However, minimal response to PTX in patients was demonstrated in several clinical trials [ 5 – 8 ].…”

“…Considering basal gene expression and through guide RNA comparison between PTX-treated versus DMSO-treated samples using differential gene expression analysis, 51 putative genes involved in PTX susceptibility were identified. The above-mentioned have an implication in pathways like NFkB, toll-like receptor, and MAPK signaling, transcriptional misregulation, and apoptosis [ 2 ].…”

“…Five of the 51 previously identified genes displayed a significant interaction between gene expression and OS in taxane-treated patients. Among them, the signal sequence receptor 3 (SSR3) gene showed to be predictive of PTX susceptibility in TCGA, giving patients a favorable OS and higher relapse-free survival when treated with taxanes [ 2 ]. In the GEO dataset, which is composed of patients who did not receive hormonal therapy or chemotherapy, SSR3 did not show to be predictive of relapse-free survival [ 2 ].…”