MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription.
MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription.
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DOI：
10.1016/j.neo.2021.06.006
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Sun SY
中科院分区：
文献类型：
--
作者：
Deng L;Vallega KA;Zhang S;Shi P;Sun SY
死亡受体4（DR 4）是一种细胞表面蛋白，通常认为其在与其名为TRAIL的配体结合后介导凋亡。然而，其对细胞凋亡抗性的贡献也有报道。MET（或c-MET）基因扩增代表了EGFR酪氨酸激酶抑制剂（EGFR-TKI）对EGFR突变型非小细胞肺癌（NSCLC）获得性耐药的重要机制。本研究的重点是证明MET抑制对MET扩增的EGFR突变NSCLC细胞系中DR 4调节的影响及其潜在机制。几种MET抑制剂降低了MET扩增的HCC 827细胞系中对EGFR-TKI耐药的DR 4水平，对调节DR 5水平没有影响或影响有限，同时增加了HCC 827亲本细胞和其他NSCLC细胞系中的DR 4水平。MET抑制剂不影响DR 4的稳定性，但降低DR 4 mRNA水平，抑制AP-1依赖性DR 4启动子的反式激活。此外，这些抑制剂抑制ERK和c-Jun磷酸化，伴随c-Jun水平降低。因此，MET抑制可能通过抑制AP-1介导的DR 4转录下调MET扩增的EGFR突变型NSCLC细胞中的DR 4表达。奥希替尼联合MET抑制可协同诱导MET扩增的EGFR突变型NSCLC细胞凋亡，并在体外和体内增强DR 4降低。此外，MET抑制与TRAIL组合增强了MET扩增的EGFR突变体HCC 827/AR细胞的杀伤，但对HCC 827亲本细胞没有增强。这些数据共同表明，DR 4可能具有未识别的抗凋亡功能，有助于在给定条件下的凋亡抗性。
Death receptor 4 (DR4) is a cell surface protein that is generally thought to mediate apoptosis upon binding to its ligand named TRAIL. However, its contribution to apoptosis resistance has also been reported. MET (or c-MET) gene amplification represents an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutant non-small cell lung cancer (NSCLC). This study focuses on demonstrating the impact of MET inhibition on DR4 modulation in MET-amplified EGFR mutant NSCLC cell lines and the underlying mechanisms. Several MET inhibitors decreased DR4 levels in MET-amplified HCC827 cell lines resistant to EGFR-TKIs with no or limited effects on modulating DR5 levels, while increasing DR4 levels in HCC827 parental cells and other NSCLC cell lines. MET inhibitors did not affect DR4 stability, but decreased DR4 mRNA levels with suppression of AP-1-dependent DR4 promoter transactivation. Moreover, these inhibitors suppressed ERK and c-Jun phosphorylation accompanied with decreasing c-Jun levels. Hence, it is likely that MET inhibition downregulates DR4 expression in MET-amplified EGFR mutant NSCLC cells through suppressing AP-1-mediated DR4 transcription. Osimertinib combined with MET inhibition synergistically induces apoptosis in the MET-amplified EGFR mutant NSCLC cells accompanied with augmented DR4 reduction both in vitro and in vivo. Furthermore, MET inhibition combined with TRAIL enhanced killing of MET-amplified EGFR mutant HCC827/AR cells, but not HCC827 parental cells. These data collectively suggest that DR4 may possess an unrecognized anti-apoptotic function, contributing to apoptosis resistance under given conditions.
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影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
7.3
作者：
O' Reilly E;Tirincsi A;Logue SE;Szegezdi E
通讯作者：
Szegezdi E
影响因子：
4.8
作者：
Oh, You-Take;Liu, Xiangguo;Sun, Shi-Yong
通讯作者：
Sun, Shi-Yong
影响因子：
4.8
作者：
Yao, Weilong;Oh, You-Take;Sun, Shi-Yong
通讯作者：
Sun, Shi-Yong
影响因子：
9.7
作者：
Shi, Puyu;Oh, You Take;Sun, Shi-Yong
通讯作者：
Sun, Shi-Yong