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 Stupp; Adam M. Sonabend

doi:10.1158/1078-0432.CCR-21-2563

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 journal › Article › peer-review

8 Scopus citations

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 language	English (US)
Pages (from-to)	3156-3169
Number of pages	14
Journal	Clinical Cancer Research
Volume	28
Issue number	14
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-2563
State	Published - Jul 15 2022

Funding

This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Győrffy was supported by the Higher Education Institutional Excellence Pro-gramme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses. V.A. Arrieta reports grants from NIH during the conduct of the study. D.Y. Zhang reports a patent for application of albumin-bound paclitaxel in combination with ultrasound for the treatment of brain tumors pending. L. Chen reports grants from NIH during the conduct of the study. P. Hsu reports other support from Spotlight Therapeutics, Moment Biosciences, Vial Health, and Serotiny outside the submitted work; in addition, P. Hsu has a patent for inventions related to CRISPR technology pending and issued. R. Stupp reports personal fees from Insightec, CranioVation, Lookwood/BlackDiamond, Northwest Biotherapeutics, AstraZeneca, Elsevier, Syneos Health, Novocure Ltd, and Boston Scientific Corporation, and personal fees and nonfinancial support from Carthera outside the submitted work. A.M. Sonabend reports a patent for 63/202,761 pending and issued to Northwestern University. No disclosures were reported by the other authors. This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Gyórffy was supported by the Higher Education Institutional Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.CCR-21-2563

Cite this

Dmello, C., Sonabend, A., Arrieta, V. A., Zhang, D. Y., Kanojia, D., Chen, L., Gould, A., Zhang, J., Kang, S. J., Winter, J., Horbinski, C., Amidei, C., Győrffy, B., Cordero, A., Chang, C. L., Castro, B., Hsu, P., Ahmed, A. U., Lesniak, M. S., ... Sonabend, A. M. (2022). Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma. Clinical Cancer Research, 28(14), 3156-3169. https://doi.org/10.1158/1078-0432.CCR-21-2563

@article{2326ce5d260346b0878c07894c030eaa,

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

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.",

author = "Crismita Dmello and Aar{\'o}n Sonabend and Arrieta, {Victor A.} and Zhang, {Daniel Y.} and Deepak Kanojia and Li Chen and Andrew Gould and Jiangshan Zhang and Kang, {Seong Jae} and Jan Winter and Craig Horbinski and Christina Amidei and Bal{\'a}zs Gy{\H o}rffy and Alex Cordero and Chang, {Catalina Lee} and Brandyn Castro and Patrick Hsu and Ahmed, {Atique U.} and Lesniak, {Maciej S.} and Roger Stupp and Sonabend, {Adam M.}",

note = "Funding Information: This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Gy{\H o}rffy was supported by the Higher Education Institutional Excellence Pro-gramme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses. Funding Information: V.A. Arrieta reports grants from NIH during the conduct of the study. D.Y. Zhang reports a patent for application of albumin-bound paclitaxel in combination with ultrasound for the treatment of brain tumors pending. L. Chen reports grants from NIH during the conduct of the study. P. Hsu reports other support from Spotlight Therapeutics, Moment Biosciences, Vial Health, and Serotiny outside the submitted work; in addition, P. Hsu has a patent for inventions related to CRISPR technology pending and issued. R. Stupp reports personal fees from Insightec, CranioVation, Lookwood/BlackDiamond, Northwest Biotherapeutics, AstraZeneca, Elsevier, Syneos Health, Novocure Ltd, and Boston Scientific Corporation, and personal fees and nonfinancial support from Carthera outside the submitted work. A.M. Sonabend reports a patent for 63/202,761 pending and issued to Northwestern University. No disclosures were reported by the other authors. Funding Information: This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Gy{\'o}rffy was supported by the Higher Education Institutional Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research",

year = "2022",

month = jul,

day = "15",

doi = "10.1158/1078-0432.CCR-21-2563",

language = "English (US)",

volume = "28",

pages = "3156--3169",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "14",

}

Dmello, C, Sonabend, A, Arrieta, VA, Zhang, DY, Kanojia, D, Chen, L, Gould, A, Zhang, J, Kang, SJ, Winter, J, Horbinski, C, Amidei, C, Győrffy, B, Cordero, A, Chang, CL, Castro, B, Hsu, P, Ahmed, AU , Lesniak, MS , Stupp, R & Sonabend, AM 2022, 'Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma', Clinical Cancer Research, vol. 28, no. 14, pp. 3156-3169. https://doi.org/10.1158/1078-0432.CCR-21-2563

TY - JOUR

T1 - Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma

AU - Dmello, Crismita

AU - Sonabend, Aarón

AU - Arrieta, Victor A.

AU - Zhang, Daniel Y.

AU - Kanojia, Deepak

AU - Chen, Li

AU - Gould, Andrew

AU - Zhang, Jiangshan

AU - Kang, Seong Jae

AU - Winter, Jan

AU - Horbinski, Craig

AU - Amidei, Christina

AU - Győrffy, Balázs

AU - Cordero, Alex

AU - Chang, Catalina Lee

AU - Castro, Brandyn

AU - Hsu, Patrick

AU - Ahmed, Atique U.

AU - Lesniak, Maciej S.

AU - Stupp, Roger

AU - Sonabend, Adam M.

N1 - Funding Information: This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Győrffy was supported by the Higher Education Institutional Excellence Pro-gramme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses. Funding Information: V.A. Arrieta reports grants from NIH during the conduct of the study. D.Y. Zhang reports a patent for application of albumin-bound paclitaxel in combination with ultrasound for the treatment of brain tumors pending. L. Chen reports grants from NIH during the conduct of the study. P. Hsu reports other support from Spotlight Therapeutics, Moment Biosciences, Vial Health, and Serotiny outside the submitted work; in addition, P. Hsu has a patent for inventions related to CRISPR technology pending and issued. R. Stupp reports personal fees from Insightec, CranioVation, Lookwood/BlackDiamond, Northwest Biotherapeutics, AstraZeneca, Elsevier, Syneos Health, Novocure Ltd, and Boston Scientific Corporation, and personal fees and nonfinancial support from Carthera outside the submitted work. A.M. Sonabend reports a patent for 63/202,761 pending and issued to Northwestern University. No disclosures were reported by the other authors. Funding Information: This work was funded by 5DP5OD021356-05 (A.M. Sonabend), 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), philanthropic support from the Moceri Family Foundation and developmental funds from The Robert H. Lurie Comprehensive Cancer Center Support Grant #P30CA060553 (A.M. Sonabend). B. Gyórffy was supported by the Higher Education Institutional Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We sincerely thank our deceased colleague Joshua Robert Kane for his contributions toward performing of experiments and data analyses. Publisher Copyright: © 2022 American Association for Cancer Research

PY - 2022/7/15

Y1 - 2022/7/15

N2 - 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.

AB - 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.

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ER -

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

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