Xingxiang Xu

INTRODUCTION: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. METHODS: Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. RESULTS: A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. CONCLUSIONS: Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

To identify and understand early events in lung carcinogenesis, we used a cDNA array to screen for genes that are expressed differentially in normal human bronchial epithelial (NHBE) cells and a tumorigenic cell line (1170-I) derived from immortalized HBE cells after exposure to cigarette smoke condensate in vivo. Among these genes, we have identified the S100A2 gene, which encodes a nuclear calcium-binding protein, as being down-regulated in the 1170-I cells. Because this gene has been implicated as a tumor suppressor in breast cancer, we examined its potential role as a tumor suppressor in lung carcinogenesis. Levels of S100A2 transcript and protein, which were high in NHBE cells, decreased by up to 50% in immortalized HBE cells (BEAS-2B and 1799) and to low to nearly undetectable levels in transformed (1198) and tumorigenic (1170-I) HBE cells. Furthermore, S100A2 mRNA and protein were undetectable in 8 and expressed at a reduced level in 3 of 11 non-small cell lung cancer (NSCLC) cell lines. Positive immunohistochemical staining of S100A2 was detected in the majority (75-83%) of normal and hyperplastic lung tissues, whereas it was detected in <10% of metaplastic lung tissues, squamous cell carcinoma, and adenocarcinoma. Treatment of 1170-I HBE and NSCLC cells with 5-aza-2'-deoxycytidine resulted in partial restoration of S100A2 expression in seven of eight cell lines. Indeed, CpG methylation was detected in the promoter region of the S100A2 gene. Our results suggest that S100A2 expression is suppressed early during lung carcinogenesis, possibly by hypermethylation of its promoter, and that its loss may be a contributing factor in lung cancer development or a biomarker of early changes in this process.

Lung cancer is the leading cause of cancer death in the world, and aberrant expression of miRNA is a common feature during the cancer initiation and development. Our previous study showed that levels of miRNA-148a assessed by quantitative real-time polymerase chain reaction (qRT-PCR) were a good prognosis factor for non-small cell lung cancer (NSCLC) patients. In this study, we used high-throughput formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays and in situ hybridization (ISH) to determine the clinical significances of miRNA-148a and aimed to find novel target of miRNA-148a in lung cancer. Our results showed that there were 86 of 159 patients with low miRNA-148a expression and miRNA-148a was significantly down-regulated in primary cancer tissues when compared with their adjacent normal lung tissues. Low expression of miRNA-148a was strongly associated with high tumor grade, lymph node (LN) metastasis and a higher risk of tumor-related death in NSCLC. Lentivirus mediated overexpression of miRNA-148a inhibited migration and invasion of A549 and H1299 lung cancer cells. Furthermore, we validated Wnt1 as a direct target of miRNA-148a. Our data showed that the Wnt1 expression was negatively correlated with the expression of miRNA-148a in both primary cancer tissues and their corresponding adjacent normal lung tissues. In addition, overexpression of miRNA-148a inhibited Wnt1 protein expression in cancer cells. And knocking down of Wnt-1 by siRNA had the similar effect of miRNA-148a overexpression on cell migration and invasion in lung cancer cells. In conclusion, our results suggest that miRNA-148a inhibited cell migration and invasion through targeting Wnt1 and this might provide a new insight into the molecular mechanisms of lung cancer metastasis.

Doxorubicin (ADR) is successfully used to treat breast cancer, however, it is often associated with the acquired resistance of breast cancer cells which eliminates the therapeutic efficiency of ADR, leading to relapse and a poorer prognosis. It has been reported that microRNA-200c (miRNA-200c), a non-coding RNA, is important in the epithelial to mesenchymal transition (EMT) and metastasis in breast cancer cells. Recent evidence demonstrated that miRNA-200c is also regulated in chemotherapeutic drug resistance, however, the precise mechanism by which this occurs remains unclear. In this study, we demonstrated that the loss of miRNA-200c correlates with the acquired resistance of breast cancer cells to ADR. In addition, the loss of miRNA-200c correlated with decreased levels of E-cadherin and PTEN, and increased levels of ZEB1 and phospho-Akt (p-Akt) in ADR-resistant breast cancer cells (MCF-7/ADR cells). More importantly, we demonstrated that the gain of miRNA-200c results in an increased sensitivity of cells to ADR, downregulation of ZEB1, upregulation of E-cadherin and PTEN, and inactivation of Akt signaling. Following the co-transfection of E-cadherin siRNA, the miRNA-200c-mediated regulation of Akt signaling and PTEN was inhibited. Results of the present study also demonstrated that Akt signaling is involved in the ADR resistance of breast cancer cells since LY294002, an inhibitor of Akt signaling, partially restored the sensitivity of MCF-7/ADR cells to ADR. In conclusion, miRNA-200c inhibited Akt signaling through its effects on E-cadherin and PTEN, resulting in the inhibition of ADR resistance in breast cancer cells.