Virtual Library
Start Your Search
HAN Rui
Author of
-
+
P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.03-27 - Aspirin Overcomes Acquired Resistance to Osimertinib in Human Lung Cancer Cells via Bim-Dependent Apoptosis Induction (ID 493)
09:45 - 18:00 | Author(s): HAN Rui
- Abstract
Background
Osimertinib, a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), provides remarkable clinical benefit for patients with EGFR-TKI sensitizing and/or EGFR T790M resistance mutations. Unfortunately, osimertinib can be changed to acquired resistance eventually occurs, which limits its clinical effects. There is currently no effective method to overcome this acquired resistance. The current study aims to identify a new method to overcome acquired osimertinib resistance.
Method
The effects of combination treatment with osimertinib and aspirin on osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines (PC-9GROR and H1975-OR) were assayed using MTT and Ki67 incorporation assays, flow cytometry, immunofluorescence staining, Western blotting analysis, and xenograft tumor implantation. Data of NSCLC patients who received osimertinib treatment in Daping hospital between January 2015 and January 2019 were reviewed retrospectively.
Result
Two patients with NSCLC who were gradually developing resistance to osimertinib began aspirin for thrombosis; a partial anti-tumor response was unexpectedly observed. The combination of osimertinib and aspirin induced strong anti-proliferative and pro-apoptotic effects in osimertinib-resistant NSCLC lines through inhibition of Akt/FoxO3a signaling phosphorylation and increased Bim expression. Furthermore, siRNA knockdown of Bim expression significantly attenuated the ability of aspirin to re-sensitize osimertinib. In vivo, the combination of aspirin and osimertinib significantly decreased tumor growth of xenografts based on the PC-9GROR cell line through inhibition of Akt/FoxO3a signaling phosphorylation and elevation of Bim. The retrospectively analyze clinical data of 45 cases of NSCLC patients showed the median progression-free survival (PFS) in osimertinib plus aspirin group patients were significantly longer than those in osimertinib alone group patients.
Conclusion
Aspirin, a generally safe and inexpensive drug, has synergistic effects with osimertinib via modulation of Bim-dependent apoptosis in osimertinib-resistant NSCLC cell lines and xenografts. It may be an effective strategy for overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.
-
+
P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.14-25 - Lorlatinib Induced Protective Autophagy via the AKT–mTOR Pathway in ALK- Rearrangement Lung Cancer Cells (Now Available) (ID 1053)
10:15 - 18:15 | Author(s): HAN Rui
- Abstract
Background
Lorlatinib, also known as PF-6463922, is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that had been approved clinic treatment with patients who failed previous ALK inhibitors. However, the growth inhibitory effects of Lorlatinib on NSCLC and the underlying mechanism.
Method
The growth inhibitory effects of Lorlatinib were investigated in H3122 and H2228 cell lines. Cell death and proliferation were assessed with MTT and Colony formation assay. Flow cytometry assays was performed to study the cell apoptosis. Cyto-ID® immunofluorescence staining was performed to study the cell autophagy. Signaling transduction was demonstrated with western blot.
Result
We observed that Lorlatinib induces cytotoxicity in H3122 and H2228 cells. trigger autophagy in both H3122 and H2228 cells by increasing the expression of phosphatidylethanolamine‐modified microtubule‐associated protein light‐chain 3 (LC3) and decreasing the expression of p62, still can trigger apoptosis by increasing the expression of B cell lymphoma 2 interacting mediator of cell death (Bim). In the presence of the autophagy blocker (chloroquine) and autophagy enhancer (rapamycin), enhanced the cytotoxicity of Lorlatinib and the Lorlatinib -induced increase in Bim was further augmented. The levels of total and phosphorylated ALK can decrease by Lorlatinib. Lorlatinib inhibited the phosphorylation of AKT and the main autophagy repressor mammalian target of rapamycin (mTOR), pharmacological inhibition of AKT by MK-2206 enhanced Lorlatinib‐induced cell death, and it increased LC3 and Bim level.
Conclusion
We demonstrated that the growth inhibitory effects of Lorlatinib on NSCLC via induced autophagy and apoptosis through AKT/ mTOR signaling pathway, and Pharmacological Intervention of Lorlatinib -induced Autophagy Enhances the Cytotoxicity of Lorlatinib. Our findings provided preliminary data for therapeutic strategies to enhance Lorlatinib efficacy in NSCLC patients.
