Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis.

Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits the clinical efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with clinical osimertinib resistance who regained a positive response after osimertinib plus anlotinib treatment. Two osimertinib-resistant cell lines were constructed, and AXL conferred resistance to osimertinib in NSCLC cell lines. The combined effects of anlotinib and osimertinib restored sensitivity to osimertinib in two osimertinib-resistant NSCLC cell lines and in xenografts. Moreover, anlotinib inhibits the phosphorylation of AXL in both resistant cell lines. Mechanistically, we confirmed that MYC binds to the promoter of AXL to promote its transcription in NSCLC cells, and we demonstrated that anlotinib combined with osimertinib treatment enhances the anti-tumor effect by inactivating the c-MET/MYC/AXL axis to reverse osimertinib resistance in NSCLC. In conclusion, our results provide strong support that this combination therapy may be effective in enhancing the efficacy of treatments in patients with advanced NSCLC.

The pseudogene DUXAP10 contributes to gefitinib resistance in NSCLC by repressing OAS2 expression.

Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI),is the currently recommended first-line therapy for advanced EGFR-mutant lung cancer, and understanding the mechanism of resistance is the key to formulating therapeutic strategies for EGFR-TKIs. In this study, we evaluate the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance. We find that pseudogene DUXAP10 expression is significantly upregulated in NSCLC gefitinib-resistant cells and tissues. Gain and loss of function assays reveal that knockdown of DUXAP10 by siRNA reverses gefitinib resistance both in vitro and in vivo. Furthermore, DUXAP10 interacts with the histone methyltransferase enhancer of zeste homolog 2 (EZH2) to repress the expression of 2',5'-oligoadenylate synthetase (OAS2). Overall, our study highlights the pivotal role of DUXAP10 in gefitinib resistance, and the DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC.

Long noncoding RNA SNHG17: a novel molecule in human cancers.

Many studies in recent years have found that dysregulation of long non-coding RNAs (lncRNAs) can contribute to disease. Small nucleolar RNA host gene 17 (SNHG17) is a novel cancer-related lncRNA of the SNHG family which is highly expressed in various tumors and may exert oncogenic functions. Several studies have demonstrated that SNHG17 is closely related to the proliferation, migration, invasion, apoptosis, and chemical drug resistance of tumor cells, and clinical studies have found an association between high SNHG17 expression and poor prognosis. In this review, we summarize relevant studies investigating SNHG17, focusing on its biological function as well as its potential value for clinical applications.

Long noncoding RNA SNHG15: A promising target in human cancers.

As oncogenes or tumor suppressor genes, lncRNAs played an important role in tumorigenesis and the progression of human cancers. The lncRNA SNHG15 has recently been revealed to be dysregulated in malignant tumors, suggesting the aberrant expression of which contributes to clinical features and regulates various oncogenic processes. We have selected extensive literature focused on SNHG15 from electronic databases, including studies relevant to its clinical significance and the critical events in cancer-related processes such as cell proliferation, apoptosis, autophagy, metastasis, and drug resistance. This review summarized the current understanding of SNHG15 in cancer, mainly focusing on the pathological features, known biological functions, and underlying molecular mechanisms. Furthermore, SNHG15 has been well-documented to be an effective diagnostic and prognostic marker for tumors, offering novel therapeutic interventions in specific subsets of cancer cells.

HEY1-mediated cisplatin resistance in lung adenocarcinoma via epithelial-mesenchymal transition.

Lung cancer is one of the most common malignancies and the leading cause of cancer-related death in the world. In patients with advanced lung adenocarcinoma who are negative for driver gene mutations, platinum-based chemotherapy represented by cisplatin remain the standard of care. Therefore, studying the mechanism behind inevitable cisplatin resistance in lung adenocarcinoma is still important. In this study, the potentially related differential expression gene for cisplatin resistance in lung adenocarcinoma was screened in the GEO database. The expression level of HEY1 in cell lines of lung adenocarcinoma was detected and HEY1 expression was up-regulated in cisplatin-resistant lung adenocarcinoma tissues and cell lines A549/DDP. Patients with high HEY1 expression have poor prognosis after cisplatin therapy. Gain and loss function assays uncovered that HEY1 could regulate the cisplatin sensitivity of NSCLC cells. In vivo experiments have confirmed that silence of HEY1 expression can induce cisplatin resistance, and epithelial-mesenchymal transition (EMT) changes occur during this process. Mechanically, HEY1 silencing significantly up-regulated E-cadherin expression and down-regulated Vimentin in A549/DDP cells. While up-regulation of HEY1 resulted in down-regulation of E-cadherin and up-regulation of Vimentin in A549 cells. Immunohistochemical experiments confirmed that E-cadherin was significantly decreased, and Vimentin expression was significantly up-regulated in cisplatin-resistant lung adenocarcinoma tissues. HEY1 can mediate the occurrence of cisplatin-acquired resistance in lung adenocarcinoma, and the possible mechanism is to regulate the EMT. The results of this study can provide a new direction and target for clinical research on the reversal of cisplatin resistance in lung adenocarcinoma.

Case Report: Long-Term Survival With Anlotinib in a Patient With Advanced Undifferentiated Large-Cell Lung Cancer and Rare Tonsillar Metastasis.

Undifferentiated large-cell lung cancer is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis. It is insensitive to chemotherapy and easily develops drug resistance. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that patients with stage IV undifferentiated large-cell lung cancer had a median overall survival (OS) of only 4 months and that those who received chemotherapy had a median OS of only 5 months longer than those who did not. For the first time, we report a case of advanced large-cell undifferentiated lung cancer with rare tonsil metastasis. The patient developed resistance after 3 months of platinum-based systemic chemotherapy and local treatment. Antiangiogenic therapy has been continuously progressing and has shown certain efficacy in treating many malignant tumors, such as lung cancer. However, there are no relevant studies or case reports on antiangiogenic therapy in the treatment of undifferentiated large-cell lung cancer. Anlotinib, an orally delivered small-molecule antiangiogenic tyrosine kinase inhibitor (TKI), was administered to this patient after chemotherapy resistance occurred, and the outcome was assessed as continued stable disease (SD). As of the last follow-up evaluation, the progression-free survival (PFS) of the patient was 21.5 months, and the OS was 27.5 months. Retrospective immunohistochemical analysis showed that the patient was positive for one of the targets of anlotinib (PDGFR). In general, the findings in this case suggest that anlotinib may be an option with good efficacy for patients with large-cell undifferentiated lung cancer after chemotherapy resistance that may have good efficacy and also suggest that PDGFR may be the target underlying this effect.