Prognostic and immunotherapeutic implications of bilirubin metabolism-associated genes in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer and accompanies high mortality rates. While the role of bilirubin metabolism in cancer is recognized, its specific impact on LUAD and patient response to immunotherapy needs to be elucidated. This study aimed to develop a prognostic signature of bilirubin metabolism-associated genes (BMAGs) to predict outcomes and efficacy of immunotherapy in LUAD. We analysed gene expression data from The Cancer Genome Atlas (TCGA) to identify survival-related BMAGs and construct a prognostic model in LUAD. The prognostic efficacy of our model was corroborated by employing TCGA-LUAD and five Gene Expression Omnibus datasets, effectively stratifying patients into risk-defined cohorts with marked disparities in survival. The BMAG signature was indeed an independent prognostic determinant, outperforming established clinical parameters. The low-risk group exhibited a more favourable response to immunotherapy, highlighted by increased immune checkpoint expression and immune cell infiltration. Further, somatic mutation profiling differentiated the molecular landscapes of the risk categories. Our screening further identified potential drug candidates preferentially targeting the high-risk group. Our analysis of critical BMAGs showed the tumour-suppressive role of FBP1, highlighting its suppression in LUAD and its inhibitory effects on tumour proliferation, migration and invasion, in addition to its involvement in cell cycle and apoptosis regulation. These findings introduce a potent BMAG-based prognostic indicator and offer valuable insights for prognostication and tailored immunotherapy in LUAD.

Potential biomarkers and resistance mechanisms of atezolizumab in a patient with lung squamous cell carcinoma.

Background: At present, only a small fraction of patients with cancer benefit from treatment with immune checkpoint inhibitors, the reasons for which are not fully understood. Monitoring molecular and immunologic changes during treatment with immune checkpoint inhibitors would help to identify potential biomarkers and mechanisms associated with resistance and guide subsequent treatment. Methods: The authors report on a patient previously treated for lung squamous cell carcinoma who received atezolizumab-based therapy for 24 months. Results & Conclusion: Analysis of samples before and after atezolizumab treatment suggested that genetic mutations in EGFR exon 20 insertion, phosphatase and PTEN and NOTCH1 as well as changes in tumor immune microenvironment may be associated with acquired resistance to immune checkpoint inhibitor therapy.

Lay abstract The authors aimed to figure out potential biomarkers and mechanisms associated with immune checkpoint inhibitor resistance by monitoring changes during treatment in a lung squamous cell cancer patient. Interestingly, EGFR exon 20 insertion, decreased PTEN copy number and NOTCH1 mutation as well as changes in CD8⁺ T cells and macrophages were observed after disease progression. Thus, the authors suggest that these changes may be associated with atezolizumab resistance.

Long-Term Survival After Salvage Thoracic Surgery on a Patient with ALK-Rearranged Metastatic Lung Adenocarcinoma After Progression on Targeted Therapy.

Targeted therapy for patients with advanced non-small cell lung cancer (NSCLC) is often challenged by the arising of drug resistance. After progression to targeted therapy, treatment options include continued targeted therapy, definitive local therapy, and the combination of both. While there is evidence that local ablative radiotherapy may prolong the disease control by targeted therapy, little is known regarding the relevance of salvage thoracic surgery in this setting. Herein, we presented a case of stage IV lung adenocarcinoma with concurrent EML4-ALK and TAC1-ALK fusion who had long-term survival after salvage thoracic surgery. The patient underwent a multidisciplinary treatment scheme that consisted of radiotherapy, ALK inhibitor crizotinib, and surgery, with blood-based genomic profiling for monitoring disease progression. Notably, salvage thoracic surgery was performed after progression on the crizotinib therapy and acquired ALK F1174C mutation was identified, which has been shown to be resistant to crizotinib and possibly sensitive to ceritinib. The patient benefited from salvage thoracic surgery with a remarkable progression-free survival of 31 months at last follow-up, and the patient maintained high-performance status throughout the course of management. To the best of our knowledge, this is the first case reporting on the long-term survival outcome from salvage thoracic surgery after crizotinib treatment in an NSCLC patient carrying double ALK fusion.

miR­10a increases the cisplatin resistance of lung adenocarcinoma circulating tumor cells via targeting PIK3CA in the PI3K/Akt pathway.

Circulating tumor cells (CTCs) that are shed from the primary tumor invade the blood stream or surrounding parenchyma to form new tumors. The present study aimed to explore the underlying mechanism of cisplatin resistance in lung adenocarcinoma CTCs and provide clinical treatment guidance for lung cancer treatment. CTCs from the blood samples of 6 lung adenocarcinoma patients were treated with different concentrations of cisplatin along with A549 and H1299 cells. The sensitivity of CTCs to cisplatin was explored by detecting the inhibitory rate via CCK­8 assay. The related molecular mechanism was investigated by western blot analysis. miR­10a expression was detected using quantitative real­time PCR (RT­qPCR). The relationship between miR­10a and phosphatidylinositol­4,5­bisphosphate 3­kinase catalytic subunit α (PIK3CA) was verified and further confirmed by luciferase reporter assay, western blotting and RT­qPCR assay. The results revealed that CTCs exhibited lower cisplatin sensitivity than A549 and H1299 cells. Moreover, CTCs treated with cisplatin demonstrated higher miR­10a expression and lower PIK3CA expression than that in A549 and H1299 cells (P<0.01). Expression of phosphoinositide 3­kinase (PI3K) and protein kinase B (Akt) phosphorylation were also decreased in A549 and H1299 cells compared with CTCs after cisplatin treatment. PIK3CA is a target of miR­10a, and both miR­10a overexpression and PIK3CA knockdown obviously decreased the sensitivity of A549 and H1299 cells to cisplatin as well as the expression of PI3K and phosphorylation of Akt. PIK3CA overexpression attenuated the cisplatin resistance of A549 and H1299 cells induced by miR­10a. In conclusion, miR­10a suppressed the PI3K/Akt pathway to strengthen the resistance of CTCs to cisplatin via targeting PIK3CA, providing a new therapeutic target for lung cancer treatment.