Background Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been used as first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, during treatment, cancer cells often develop resistance to gefitinib, the mechanisms of which are not fully understood. This study was designed to elucidate the expression and role of long non-coding RNA (lncRNA)-PCAT-1, a potential biomarker for drug resistance and a therapeutic target for NSCLC, in gefitinib resistance in NSCLC cells. Methods In this study, we verified differential PCAT-1 expression in NSCLC gefitinib-resistant tissues or cells. PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence assays were used to verify the correlation between PCAT-1 and gefitinib sensitivity. A nude mouse tumor-bearing model verified that PCAT-1 can reverse gefitinib resistance in vivo. Then, a PI3K/Akt agonist was used to verify the possible mechanism of PCAT-1 action. Results PCAT-1 is highly expressed in gefitinib-resistant NSCLC tissues and cells. PCAT-1 knockdown enhanced gefitinib sensitivity and gefitinib-induced apoptosis in H1299/GR cells. PCAT-1 knockdown reduced tumor volume and weight, and reversed acquired gefitinib resistance in vivo. PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation in H1299/GR cells. A PI3K/AKT agonist reversed PCAT-1 knockdown-mediated enhancement of gefitinib sensitivity in H1299/GR cells Conclusion PCAT-1 knockdown improves sensitivity to gefitinib by inhibition of AKT and GSK3 phosphorylation in NSCLC. PCAT-1 is as potential target for improving the clinical efficacy of gefitinib.
Background Hyper-progressive disease (HPD) is an unexpected response pattern observed in immune checkpoint therapy, such patients experience a very rapid disease progression (usually progressed seriously in three months). Predictors of HPD are one of the keys to the management of patients receiving immune checkpoint inhibitors. Some factors, such as MDM2/4 amplification, EGFR mutations and old age may be risk factors for HPD, but the results of different studies are inconsistent. Herein, we evaluated the characteristics of MDM2/4 alterations in Chinese patients with NSCLC. Methods The formalin-fixed paraffin-embedded specimens of cancer patients who have underwent next-generation sequencing (NGS) in 3D Medicines, a laboratory accredited by CAP and Clinical Laboratory Improvement Amendments (CLIA) from May 2017 to May 2020, were included in this study. NGS was performed to detect gene mutation, and tumor mutational burden (TMB) measured by a 733 gene panel. PD-L1 expression detected by using Dako PD-L1 IHC 22C3 pharmDx. Results The proportion of MDM2/4 amplification in Chinese NSCLC patients is 0.86%, the proportion of MDM2 and MDM4 amplification in Chinese NSCLC patients were 0.74% and 0.12%. respectively. Further analysis found lower TMB level in patients with MDM2/4 amplification than patients without MDM2/4 amplification (p<0.001). The median TMB level was also found lower in patients with MDM2/4 amplification than without, and higher ratio of patients with TMB-high (defined as TMB≥10mutant/Mb) was displayed in group with MDM2/4 amplification. Conversely, patients with TMB-high showed lower copy number gain in MDM2/4. However, no difference was found in level of PD-L1 expression between patients with and without MDM2/4 amplification. Conclusion HPD happened during ICI treatment in solid tumor with MDM2/4 amplification may associated with lower TMB level, and PD-L1 expression level has limit effect on MDM2/4 alteration related HPD. Citation Format: Xudong Xiang, Hushan Zhang, Deguang Wang, Heng Li, Qing Lei, Qianli Ma. Analysis of genetic alterations related to hyper-progressive disease after immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5100.
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