时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
However, clinical translation of single-agent inhibitors targeting these pathways, such as γ-secretase inhibitors and PI3K/AKT/mTOR inhibitors, has been hampered by suboptimal efficacy and dose-limiting toxicities [, , ].；However, the optimal strategy to exploit this vulnerability in T-ALL remains unclear, and biomarkers to identify patients most likely to benefit are lacking.；Given that c-MYC is a key driver of ribosome biogenesis, we hypothesized that osimertinib-mediated c-MYC suppression would impair this anabolic process.
方法
Protein concentration was measured by bicinchoninic acid (BCA) assay (P0012, Beyotime, China).；For MG132 treatment, cells were pre-treated with MG132 (0.5 µM) for 2 h followed by osimertinib (5 µM) for 12 h.；For the combination plus CHX group, cells were treated with the combination for 12–24 h, followed by CHX (10 µg/mL) 1 h before sample collection.；Quantitative PCR was performed on a CFX96 Touch Real-Time PCR Detection System (Bio-Rad) using SYBR Green qPCR Master Mix (K0221, Thermo, USA).
核心结论
Osimertinib induced dose-dependent cytotoxicity in all four cell lines at 24 and 48 h, with half-maximal inhibitory concentration (IC50) values at 24 h of 6.5 µM in MOLT-4, 2.8 µM in Jurkat, 4.6 µM in CCRF/CEM, and 3.5 µM in MOLT-3, and lower IC50 values at 48 h (Fig.；Low-dose osimertinib (0.5, 1, and 2 µM) alone induced minimal apoptosis, whereas 5 or 10 µM osimertinib significantly increased Annexin V-positive cells at 24 h and induced cleavage of PARP1 and caspase-3 in all four cell lines (Figs.；Cell death was caspase-dependent; the pan-caspase inhibitor Z-VAD-FMK significantly blocked osimertinib-induced apoptosis (Fig. ‖ 结论：Larger cohorts of primary T-ALL samples are therefore needed to confirm the generalizability of our findings.
局限
Together with the lack of EGFR expression and the inability of EGF to rescue apoptosis, these data indicate a non-canonical, EGFR-independent mechanism for osimertinib-induced c-MYC degradation, although the direct molecular target remains to be identified.；Therefore, further studies with pharmacokinetic monitoring and PDX models are needed to determine whether clinically achievable concentrations produce similar anti-leukemic effects in vivo.；Several limitations of this study warrant consideration.
对本项目的价值
★☆☆☆☆ 干预证据决定参照标准效应量——任何抗衰干预的收益至少应对标该基线。
全文来源
PMC JATS 全文（正文 47,523 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.
- 期刊与标识：Biomark Res · PMID 42958372 · DOI 10.1186/s40364-026-01031-w
A 级证据分级：A 级（同行评议人体研究）
本文属人体研究证据，但需注意：观察性或小样本干预的结论不等于已证实临床获益；效应量与长期安全性仍需更大规模、更长随访的试验验证。
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