EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.
EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.
复制标题
EGFR 信号传导定义了神经母细胞瘤中 Mcl‐1 的生存依赖性。
DOI：
10.1080/15384047.2014.1002333
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发表时间：
2015
影响因子：
3.6
通讯作者：
Goldsmith,KellyC
中科院分区：
文献类型：
--
作者：
Nalluri,Srilatha;Peirce,SusanK;Tanos,Rachel;Abdella,HaneenA;Karmali,Dipan;Hogarty,MichaelD;Goldsmith,KellyC
小儿实体瘤神经母细胞瘤（NB）通常依赖于抗凋亡蛋白Mcl-1通过Mcl-1隔离促凋亡Bim而存活。目前尚不存在高亲和力Mcl-1抑制剂，因此临床上对抑制Mcl-1的新方法的需求很高。受体酪氨酸激酶（RTK）在许多癌症中调节Mcl-1并在NB存活中起作用，但它们如何调节NB中Bcl-2家族的相互作用尚不清楚。我们发现，NB细胞系衍生抵抗Bcl-2/-xl/-w拮抗剂，ABT-737，获得对Mcl-1的依赖性，并显示增加的RTK，EGFR的表达和激活。与依赖Bcl-2的细胞系相比，在诊断时和复发后来自相同肿瘤的Mcl-1依赖性NB细胞系也具有增加的EGFR表达。在Mcl-1依赖性NB中通过shRNA或厄洛替尼抑制EGFR破坏Bim与Mcl-1的结合并增强其对Bcl-2的亲和力，恢复对ABT-737的敏感性以及体外细胞毒性。用EGFR（厄洛替尼、西妥昔单抗）和ERK（U 0126）的小分子抑制剂机械治疗NB增加Noxa表达并使Bim去磷酸化以促进Bim与Bcl-2结合。因此，EGFR通过ERK介导的Bim磷酸化调节高危NB中的Mcl-1依赖性，使得EGFR/ERK抑制使得Mcl-1依赖性肿瘤现在依赖于Bcl-2。在临床上，EGFR抑制剂作为单一药剂化合物在复发性NB患者中是无效的，可能是由于这种转移的对Bcl-2的存活依赖性。同样，EGFR或ERK抑制剂与Bcl-2拮抗剂的体内组合作为一种新的未来组合以克服临床中的治疗抗性，需要进一步测试。
The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl-1, for survival through Mcl-1 sequestration of pro-apoptotic Bim. High affinity Mcl-1 inhibitors currently do not exist such that novel methods to inhibit Mcl-1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl-1 in many cancers and play a role in NB survival, yet how they regulate Bcl-2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl-2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl-1 and show increased expression and activation of the RTK, EGFR. Mcl-1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl-2. Inhibition of EGFR by shRNA or erlotinib in Mcl-1 dependent NBs disrupts Bim binding to Mcl-1 and enhances its affinity for Bcl-2, restoring sensitivity to ABT-737 as well as cytotoxicsin vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl-2. Thus, EGFR regulates Mcl-1 dependence in high-risk NB via ERK-mediated phosphorylation of Bim such that EGFR/ERK inhibition renders Mcl-1 dependent tumors now reliant on Bcl-2. Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl-2. Likewise, EGFR or ERK inhibitors warrant further testing in combination with Bcl-2 antagonistsin vivoas a novel future combination to overcome therapy resistance in the clinic.