DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.

The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.

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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 Lorlatinibinduced 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.