SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status.
Kenji M FujiharaMariana Corrales BenitezCarlos S CabalagBonnie Z ZhangHyun Soo KoDavid S LiuKaylene J SimpsonYgal HauptLara LiptonSue HauptWayne A PhillipsNicholas James ClemonsPublished in: Molecular cancer therapeutics (2021)
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.
Keyphrases
- clinical trial
- gene expression
- squamous cell carcinoma
- end stage renal disease
- newly diagnosed
- dna methylation
- stem cells
- transcription factor
- papillary thyroid
- peritoneal dialysis
- randomized controlled trial
- radiation therapy
- endoplasmic reticulum stress
- microbial community
- genome wide
- copy number
- liver injury
- case report
- bone marrow
- smoking cessation
- liver fibrosis
- patient reported
- antibiotic resistance genes
- drug induced
- chemotherapy induced