Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Death Dis. 2020 Oct 20;11(10):884. doi: 10.1038/s41419-020-03098-1.
Resistance to molecular therapies frequently occur due to genetic changes affecting the targeted pathway. In myeloid and lymphoid leukemias/lymphomas resulting from constitutive activation of FGFR1 kinases, resistance has been shown to be due either to mutations in FGFR1 or deletions of PTEN. RNA-Seq analysis of the resistant clones demonstrates expression changes in cell death pathways centering on the p53 upregulated modulator of apoptosis (Puma) protein. Treatment with different tyrosine kinase inhibitors (TKIs) revealed that, in both FGFR1 mutation and Pten deletion-mediated resistance, sustained Akt activation in resistant cells leads to compromised Puma activation, resulting in suppression of TKI-induced apoptosis. This suppression of Puma is achieved as a result of sequestration of inactivated p-Foxo3a in the cytoplasm. CRISPR/Cas9 mediated knockout of Puma in leukemic cells led to an increased drug resistance in the knockout cells demonstrating a direct role in TKI resistance. Since Puma promotes cell death by targeting Bcl2, TKI-resistant cells showed high Bcl2 levels and targeting Bcl2 with Venetoclax (ABT199) led to increased apoptosis in these cells. In vivo treatment of mice xenografted with resistant cells using ABT199 suppressed leukemogenesis and led to prolonged survival. This in-depth survey of the underlying genetic mechanisms of resistance has identified a potential means of treating FGFR1-driven malignancies that are resistant to FGFR1 inhibitors.
由于影响靶向途径的遗传变化，分子疗法的耐药性经常发生。在由 FGFR1 激酶组成性激活引起的髓系和淋巴白血病/淋巴瘤中，耐药性是由于 FGFR1 突变或 PTEN 缺失引起的。耐药克隆的 RNA-Seq 分析表明，细胞死亡途径的表达变化集中在 p53 上调凋亡调节剂（Puma）蛋白上。用不同的酪氨酸激酶抑制剂（TKI）治疗表明，在 FGFR1 突变和 Pten 缺失介导的耐药性中，耐药细胞中持续的 Akt 激活导致 Puma 激活受损，从而抑制 TKI 诱导的细胞凋亡。这种对 Puma 的抑制是由于失活的 p-Foxo3a 在细胞质中的隔离实现的。CRISPR/Cas9 介导的白血病细胞中 Puma 的敲除导致敲除细胞的耐药性增加，证明了其在 TKI 耐药性中的直接作用。由于 Puma 通过靶向 Bcl2 促进细胞死亡，TKI 耐药细胞显示出高 Bcl2 水平，并用 Venetoclax（ABT199）靶向 Bcl2 导致这些细胞中的凋亡增加。用 ABT199 对携带耐药细胞的小鼠进行体内治疗抑制了白血病发生并延长了存活时间。对耐药性的潜在遗传机制的深入调查确定了一种治疗 FGFR1 驱动的恶性肿瘤的潜在方法，这些肿瘤对 FGFR1 抑制剂耐药。
