APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency

作者：Tsai, Cheng-Yu; Sun, Si; Zhang, Hongying; Local, Andrea; Su, Yongxuan; Gross, Larry A.; Rice, William G.; Howell, Stephen B.^*

来源：Molecular Cancer Therapeutics, 2018, 17(6): 1167-1176.

DOI：10.1158/1535-7163.MCT-17-0834

• MAINTENANCE THERAPY
• TRANSPORTER 1
• DAMAGE
• EXPRESSION
• MUTATIONS
• LETHALITY
• KLF4

APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)(3)]. The intracellular content of Fe(253)(3) exceeded that of the native drug by approximately 18-fold, and Fe(253)(3) appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)(3). RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression.

• 出版日期2018-6
• 单位华中科技大学