SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status
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Abstract
APR-246 (eprenetapopt) is in clinical development with a focus on hematologic malignancies and is promoted as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most APR-246 clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with doublet chemotherapy [cisplatin and 5-fluorouracil (5-FU)] in metastatic esophageal cancer, together with previous preclinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for APR-246 response. This study aims to identify a robust biomarker for response to APR-246. Correlation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression, and metabolite abundance across over 700 cancer cell lines (CCL) was performed. Functional validation and a boutique siRNA screen of over 850 redox-related genes were also conducted. TP53 mutation status was not consistently predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53, and c-Myc, were confirmed to also regulate cancer-cell sensitivity to APR-246. In conclusion, SLC7A11 expression is a broadly applicable determinant of sensitivity to APR-246 across cancer and should be utilized as the key predictive biomarker to stratify patients for future clinical investigation of APR-246.
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SLC7A11 expression is a superior determinant of response to eprenetapopt across cancer lineages, surpassing TP53 mutation status and p53 protein levels.
“Recently, we demonstrated that the expression of SLC7A11, which encodes the functional subunit of the cystine-glutamate antiporter, system xc−, is a superior determinant of response to eprenetapopt across cancer lineages, surpassing both TP53 mutation status and p53 protein levels (6).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [6]
GSH depletion and/or factors that regulate GSH availability are central determinants of eprenetapopt activity in cancer cells, as opposed to p53 and associated apoptotic machinery.
“Our work supports previous findings reporting that GSH depletion and/or factors that regulate GSH availability are central determinants of eprenetapopt activity in cancer cells (6–8), as opposed to p53 and associated apoptotic machinery.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [6]
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- Authors
- Fujihara, K. M., Corrales Benitez, M., Cabalag, C. S., Zhang, B. Z., Ko, H. S., Liu, D. S., Simpson, K. J., Haupt, Y., Lipton, L., Haupt, S., Phillips, W. A., & Clemons, N. J.
- Affiliations
- The University of Melbourne (AU)
- 1Gastrointestinal Cancer Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Fujihara, Kenji M.
- Clemons, Nicholas J.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2021-07-26
- Volume
- 20
- Issue
- 10
- Pages
- 1858-1867
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W3184587083
- Cited by
- 48
- References
- 48
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 2 · 2020: 1
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- NMHRC (APP1120293)
- Grand-In-Aid (APP1156945)
- Cancer Council Victoria
- Translational Research Project (TRP15012, MCRF16002)
- Victorian Cancer Agency Fellowship
- Australian Research Training Program
- The Alan & Kate Gibson Research Fellowship
- The Victorian Centre for Functional Genomics.
- Australian Cancer Research Foundation
- Phenomics Australia
- Australian Government's National Collaborative Research Infrastructure Strategy
- Peter MacCallum Cancer Centre Foundation
- University of Melbourne Research Collaborative Infrastructure Program
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- APR-246, SLC7A11, TP53 mutation, predictive biomarkers, mutant p53 reactivation, PRIMA-1, redox metabolism, ATF4, MDM2, c-Myc, cancer cell line sensitivity, esophageal cancer, siRNA screen, drug response
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Esophageal Neoplasms, Fluorouracil, Humans, Mutation, Prognosis, Quinuclidines, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Proteome, Amino Acid Transport System y+, Cell Proliferation, Metabolome, Transcriptome
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