TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target
TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target
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TRIB3-EGFR 相互作用促进肺癌进展并确定治疗靶点
DOI：
10.1038/s41467-020-17385-0
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发表时间：
2020-07-21
影响因子：
16.6
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Yu, Jiao-jiao;Zhou, Dan-dan;Hu, Zhuo-Wei
表皮生长因子受体（EGFR）的高表达或异常激活与肿瘤进展和癌症类型（包括非小细胞肺癌（NSCLC））的治疗耐药性相关。EGFR酪氨酸激酶抑制剂（TKI）是NSCLC的一线治疗药物。然而，患者在不可避免地获得EGFR TKI耐药突变后最终恶化，突出了对具有替代作用机制的治疗剂的需求。在这里，我们报告说，升高的tribbles假激酶3（TRIB 3）与EGFR的稳定性和NSCLC进展呈正相关。TRIB 3与EGFR相互作用并募集PKCα，以诱导EGFR质膜区域的Thr 654磷酸化和WWP 1诱导的Lys 689泛素化，从而增强EGFR再循环、稳定性、下游活性和NSCLC干性。干扰TRIB 3-EGFR与钉合肽的相互作用通过加速EGFR降解来减弱NSCLC进展，并使NSCLC细胞对化疗剂敏感。这些发现表明，靶向EGFR降解是EGFR相关NSCLC中以前未被认可的治疗选择。
High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.