MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
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DOI：
10.1038/s41467-019-11371-x
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发表时间：
2019-08-02
影响因子：
16.6
通讯作者：
Sos, Martin L.
中科院分区：
文献类型：
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作者：
Dammed, Marcel A.;Bragelmann, Johannes;Sos, Martin L.
MYC旁系同源物在小细胞肺癌（SCLC）中经常被激活，但代表了较差的药物靶点。因此，详细绘制MYC特异性脆弱性可能有助于为SCLC患者开发有效的治疗方法。使用独特的细胞CRISPR激活模型，我们发现，与MYCN和MYCL相反，MYC通过与MIZ1和DNMT3a相互作用抑制BCL 2转录。由此导致的BCL 2表达的缺乏促进了对细胞周期控制抑制的敏感性和对MCL 1的依赖性。此外，MYC激活导致细胞凋亡引发、内在遗传毒性应激和对DNA损伤检查点抑制剂的易感性增加。最后，联合AURK和CHK1抑制显著延长了携带MYC驱动的SCLC的小鼠的存活率，超过了联合化疗的存活率。这些分析揭示了MYC特异性调节细胞凋亡机制，并对SCLC患者中基于基因型的靶向治疗选择产生影响。
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.