Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.
Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.
复制标题
BCL2L1 和 MCL1 的双重抑制对于 RET 融合阳性或 MET 外显子 14 跳跃突变阳性肺腺癌细胞非常有效。
DOI：
10.1016/j.bbrc.2022.09.039
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Sakuma Y.
中科院分区：
文献类型：
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作者：
Hirai S;Idogawa M;Sumi T;Yamaguchi M;Niki T;Sakuma Y.
非小细胞肺癌（NSCLC），特别是肺腺癌（LUAD），含有几种驱动突变，高效酪氨酸激酶抑制剂（TKI）可用于治疗这些突变。虽然TKI通常对某些NSCLC有效，但几乎总是会产生原发性或获得性耐药性。驱动突变包括RET融合（NSCLC病例的10.1 -2%）和METexon 14跳跃突变（METΔ ex 14; 10.3 -4%）。令人惊讶的是，具有CCDC 6-RET融合的LUAD细胞系LC-2/ad的繁荣独立于RET信号传导，并且具有MET Δ ex 14+扩增的Hs-746 T细胞存活于MET沉默。然而，这两种细胞系对代表性抗凋亡BCL 2家族成员BCL 2L 1和MCL 1的双重沉默高度敏感，在单层或3D顶部培养系统中经历广泛的凋亡。此外，我们发现大多数LUAD细胞系和组织表达高水平的BCL 2L 1和MCL 1 mRNA，但BCL 2的表达水平极低。总之，这些发现表明，抑制BCL 2L 1加MCL 1可能代表了一种治疗LUAD细胞的新方法，而不管其驱动突变如何。
Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations includeRETfusion (∼1–2% of NSCLC cases) andMETexon 14 skipping mutation (METΔex14; ∼3–4%). Surprisingly, the LUAD cell line LC-2/ad withCCDC6-RETfusion thrived independently of RET signaling, and Hs-746T cells harboringMETΔex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels ofBCL2L1andMCL1mRNA but extremely low levels ofBCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.