SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• APR-246 (eprenetapopt) is a mutant-p53 reactivation therapy primarily investigated for hematologic malignancies.
• TP53 mutation status is currently a key criterion for patient selection in APR-246 clinical trials.
• Emerging data suggest TP53 mutation status alone may be insufficient for predicting APR-246 efficacy.

Purpose of the Study:

• To identify a robust predictive biomarker for response to APR-246 (eprenetapopt).
• To evaluate the utility of TP53 mutation status versus other molecular markers in predicting APR-246 sensitivity.
• To determine the role of SLC7A11 expression as a predictive biomarker for APR-246.

Main Methods:

• Correlation analysis of PRIMA-1 (APR-246 precursor) activity with molecular data (mutation, gene/protein expression, metabolite abundance) across over 700 cancer cell lines.
• Functional validation studies and a siRNA screen of over 850 redox-related genes.
• Assessment of genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53, and c-Myc, in relation to APR-246 sensitivity.

Main Results:

• TP53 mutation status was not consistently predictive of response to APR-246.
• SLC7A11 expression, encoding the cystine/glutamate transporter, emerged as a superior determinant of APR-246 response.
• Expression levels of SLC7A11 regulators (ATF4, MDM2, wild-type p53, c-Myc) also correlated with cancer cell sensitivity to APR-246.

Conclusions:

• SLC7A11 expression is a broadly applicable determinant of sensitivity to APR-246 across various cancer types.
• SLC7A11 should be utilized as the primary predictive biomarker for stratifying patients in future APR-246 clinical trials.
• This finding may improve patient selection and treatment outcomes for APR-246 therapy.