Anti-Human EGFR monoclonal antibody

Cancer patients who initially benefit from Erlotinib, a drug targeting EGFR path, eventually develop resistance to the drug. The underlying mechanism is largely unknown. This study investigated the role of ARL4C in Erlotinib resistance development of NSCLC. qRT-PCR and Western blotting were performed to analyze the expression of mRNA and protein of ARL4C in two NSCLC cell lines (HCC827 and PC-9). Several assays (MTS, colony formation, transwell migration, luciferase reporter, and chromatin-immunoprecipitation) were used to explore the role of ARL4C in biofunctional changes of Erlotinib-resistant cells and their associations with Jak2/Stat 5/beta-catenin signaling. Results demonstrated that (1) long-term use of Erlotinib resulted in downregulation of ARL4C; (2) overexpression of ARL4C could regain the sensitivity to Erlotinib in the drug-resistant HCC827/ER cells, while downregulation of ARL4C increased HCC827, and PC-9 cells' resistance to the drug; (3) Erlotinib-induced downregulation of ARL4C resulted in phosphorylation of Jak2/Stat5 and upregulation of beta-catenin and their related molecules Axin2, CD44, Ccnd1, Lgr-5, and MMP7, which promoted the malignant behaviors of Erlotinib-resistant cells; (4) chromatin immunoprecipitation and luciferase reporter assay revealed that Stat5 could bind to beta-catenin promoter to upregulate molecules to maintain the malignant behaviors, which might count for how Erlotinib-resistant cell survived while EGFR path was blocked; (5) the expression of ARL4C was not associated with known EGFR gene mutations in both Erlotinib-resistant cells and NSCLC tissues. Our data suggest that Erlotinib resistance of NSCLCs is associated with downregulation of ARL4C via affecting Jak/Stat/beta-catenin signaling. ARL4C could serve as a biomarker to predict the effectiveness of TKI targeting therapy and a potential therapeutic target for overcoming Erlotinib resistance in NSCLC.

Background: Existing guidelines are inconsistent regarding the indications for staging brain MRI in patients with newly diagnosed, early-stage non-small cell lung cancer (NSCLC). Purpose: To evaluate the diagnostic yield of staging brain MRI in the initial evaluation of lung cancer. Materials and Methods: This retrospective, observational, single-institution study included patients with newly diagnosed NSCLC who underwent staging chest CT and staging brain MRI from November 2017 to October 2018. Diagnostic yield was defined as the proportion of patients with brain metastases among all patients. Yield was stratified into clinical stage groups per the eighth edition of the American Joint Committee on Cancer staging guidelines, based on staging chest CT and in adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation and anaplastic lymphoma kinase (ALK) gene rearrangement. Subgroup analyses were performed on the basis of cell types and molecular markers. The chi(2) test was performed to compare the diagnostic yields, and Bonferroni correction was used to account for multiple testing between stage groups. Results: A total of 1712 patients (mean age, 64 years 6 10 [standard deviation]; 1035 men) were included. The diagnostic yield of staging brain MRI in newly diagnosed NSCLC was 11.9% (203 of 1712; 95% confidence interval [CI]: 10.4%, 13.5%). In clinical stage IA, IB, and II disease, the diagnostic yields were 0.3% (two of 615; 95% CI: 0.0%, 1.2%), 3.8% (seven of 186; 95% CI: 1.5%, 7.6%), and 4.7% (eight of 171; 95% CI: 2.0%, 9.0%), respectively. The diagnostic yield was higher in patients with adenocarcinoma (13.6%; 176 of 1297; 95% CI: 11.8%, 15.6%) than squamous cell carcinoma (5.9%; 21 of 354; 95% CI: 3.7%, 8.9%) and in patients with EGFR mutation-positive adenocarcinoma (17.5%; 85 of 487; 95% CI: 14.2%, 21.1%) than with EGFR mutation negative adenocarcinoma (10.6%; 68 of 639; 95% CI: 8.4%, 13.3%) (P<.001 for both). Conclusion: The diagnostic yield of staging brain MRI in clinical stage IA non-small cell lung cancer was low, but staging brain MRI had a higher diagnostic yield in clinical stage IB and epidermal growth factor receptor mutation-positive adenocarcinoma. (C) RSNA, 2020