SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than <i>TP53</i> Mutation Status
Kenji M. Fujihara, Mariana Corrales Benitez, Carlos S. Cabalag, Bonnie Z. Zhang, Hyun Soo Ko, David S. Liu, Kaylene J. Simpson, Ygal Haupt, Lara Lipton, Sue Haupt, Wayne A. Phillips, Nicholas J. Clemons
Abstract
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.