RESUMEN
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.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mutación , Proteína p53 Supresora de Tumor/genética , Sistema de Transporte de Aminoácidos y+/genética , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Cisplatino/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Fluorouracilo/administración & dosificación , Humanos , Metaboloma , Pronóstico , Proteoma , Quinuclidinas/administración & dosificación , Transcriptoma , Células Tumorales CultivadasRESUMEN
The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.