Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC.
Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC.
复制标题
保护性自噬通过 Foxo3a 依赖性抑制 NSCLC 细胞凋亡来降低洛拉替尼的细胞毒性
DOI：
10.1038/s41420-022-01027-z
复制
发表时间：
2022-04-22
影响因子：
7
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Lu C;Yu R;Zhang C;Lin C;Dou Y;Wu D;Pan Y;Peng T;Tang H;Han R;He Y
洛拉替尼是一种很有前途的第三代间变性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂(TKI)，已被批准用于治疗ALK阳性、既往ALK-TKI治疗失败的非小细胞肺癌(NSCLC)患者。然而，不可避免的后天抵抗力的出现限制了其长期效力。更全面地了解劳拉替尼的获得性耐药机制将有助于开发更有效的治疗策略。采用CCK-8、集落形成、免疫荧光染色、流式细胞仪分析、Western印迹分析和异种移植等方法评价氯喹(CQ)联合劳拉替尼对ALK阳性NSCLC细胞的体内外疗效。在这里，我们展示了劳拉替尼诱导ALK阳性NSCLC细胞的凋亡和保护性自噬。然而，保护性自噬可以逐渐导致劳拉替尼在ALK阳性的NSCLC细胞中的细胞毒性降低。同时，我们发现劳拉替尼与自噬抑制剂CQ在体内外均能抑制自噬，促进细胞凋亡，通过Foxo3a的去磷酸化使细胞对劳拉替尼敏感，并促进核转位，进而激活Foxo3a/Bim轴。综上所述，我们的结果提示，抑制保护性自噬可能是延缓ALK阳性NSCLC患者对劳拉替尼获得性耐药发生的治疗目标。
Lorlatinib is a promising third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that has been approved for treating ALK-positive non-small-cell lung cancer (NSCLC) patients with previous ALK-TKI treatment failures. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A more comprehensive understanding of the acquired resistance mechanisms to lorlatinib will enable the development of more efficacious therapeutic strategies. The efficacy of chloroquine (CQ) in combination with lorlatinib in ALK-positive NSCLC cells in vitro and in vivo was assessed using CCK-8, colony formation, immunofluorescence staining, flow cytometry analysis, western blot analysis, and xenograft implantation. Here, we show that lorlatinib induced apoptosis and protective autophagy in ALK-positive NSCLC cells. However, the protective autophagy can gradually lead to decreased cytotoxicity of loratinib in ALK-positive NSCLC cells. Meanwhile, we found that the combination of lorlatinib and CQ, an inhibitor of autophagy, inhibited autophagy and promoted apoptosis both in vitro and in vivo, which sensitized cells to lorlatinib through the dephosphorylation of Foxo3a and promoted nuclear translocation, then activation of Foxo3a/Bim axis. Taken together, our results suggest that inhibition of protective autophagy might be a therapeutic target for delaying the occurrence of acquired resistance to lorlatinib in ALK-positive NSCLC patients.
登录
查看更多内容
DOI：
10.1056/nejmoa1508887
发表时间：
2016-01-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Shaw AT;Friboulet L;Leshchiner I;Gainor JF;Bergqvist S;Brooun A;Burke BJ;Deng YL;Liu W;Dardaei L;Frias RL;Schultz KR;Logan J;James LP;Smeal T;Timofeevski S;Katayama R;Iafrate AJ;Le L;McTigue M;Getz G;Johnson TW;Engelman JA
通讯作者：
Engelman JA
FOXO3a 在致癌过程中的关键作用
影响因子：
37.3
作者：
Liu Y;Ao X;Ding W;Ponnusamy M;Wu W;Hao X;Yu W;Wang Y;Li P;Wang J
通讯作者：
Wang J
影响因子：
20.4
作者：
Huber, Rudolf M.;Hansen, Karin H.;Camidge, D. Ross
通讯作者：
Camidge, D. Ross
影响因子：
158.5
作者：
Solomon, Benjamin J.;Mok, Tony;Waqar, S.
通讯作者：
Waqar, S.
影响因子：
28.2
作者：
Lin JJ;Riely GJ;Shaw AT
通讯作者：
Shaw AT