Sidney Kimmel Comprehensive Cancer Center and.
Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.
Blood Adv. 2019 Mar 26;3(6):908-916. doi: 10.1182/bloodadvances.2018022921.
An intriguing aspect of the clinical activity of FMS-like tyrosine kinase 3 inhibitors (FLT3 TKIs) is their apparent higher activity against peripheral blasts from FLT3/internal tandem duplication (ITD) acute myeloid leukemia than marrow disease in the same patients. Accordingly, studies showed that the bone marrow microenvironment plays a role in FLT3 TKI resistance, although the underlying mechanisms are unclear. We recently identified a previously undescribed mechanism by which the bone marrow microenvironment can contribute to drug resistance: expression of cytochrome P450 enzymes (CYPs). In fact, bone marrow stromal cells (BMSCs) expressed most CYPs, including CYP3A4. Because hepatic CYP3A4 plays a role in the inactivation of several FLT3 TKIs, we explored the potential role of CYP3A4 in bone marrow microenvironment-mediated FLT3 TKI resistance. We found that CYP3A4 plays a major role in BMSC-mediated inhibition in the activity of 3 different FLT3 TKIs (sorafenib, quizartinib, and gilteritinib) against FLT3/ITD acute myeloid leukemia (AML). Furthermore, clarithromycin, a clinically active CYP3A4 inhibitor, significantly reversed the protective effects of BMSCs. We show, for the first time, that bone marrow stromal CYP3A4 contributes to FLT3 TKI resistance in the bone marrow. These results suggest that combining FLT3 TKIs with CYP3A4 inhibitors could be a promising strategy toward improving the activity of FLT3 TKIs.
成纤维细胞生长因子受体样酪氨酸激酶 3 抑制剂（FLT3 TKIs）的临床活性有一个有趣的方面，即它们对 FLT3/内部串联重复（ITD）急性髓系白血病患者外周blasts 的活性明显高于骨髓疾病。因此，研究表明骨髓微环境在 FLT3 TKI 耐药中起作用，尽管其潜在机制尚不清楚。我们最近发现了骨髓微环境可以导致耐药性的一个以前未描述的机制：细胞色素 P450 酶（CYPs）的表达。事实上，骨髓基质细胞（BMSCs）表达大多数 CYP，包括 CYP3A4。由于肝 CYP3A4 在几种 FLT3 TKIs 的失活中起作用，我们探讨了 CYP3A4 在骨髓微环境介导的 FLT3 TKI 耐药中的潜在作用。我们发现 CYP3A4 在 BMSC 介导的对 3 种不同的 FLT3 TKI（索拉非尼、quizartinib 和 gilteritinib）对 FLT3/ITD 急性髓系白血病（AML）活性的抑制中起主要作用。此外，克拉霉素，一种临床活性的 CYP3A4 抑制剂，显著逆转了 BMSCs 的保护作用。我们首次表明，骨髓基质 CYP3A4 有助于骨髓中的 FLT3 TKI 耐药。这些结果表明，将 FLT3 TKIs 与 CYP3A4 抑制剂联合使用可能是提高 FLT3 TKI 活性的一种有前途的策略。
