Integrin alpha 2 is associated with tumor progression and postoperative recurrence in non-small cell lung cancer.

BACKGROUND: Integrins are transmembrane proteins that mediate cell adhesion to extracellular matrix. Whereas expression of integrin alpha 2 is associated with motility, invasiveness and cellular differentiation in various tumors, the role of integrin alpha 2 in lung cancer has not been studied in detail. The aim of this study was to determine whether and how aberrant integrin alpha 2 expression in non-small cell lung cancer leads to different outcomes. METHODS: We measured expression of integrin alpha 2 by quantitative polymerase chain reaction in 100 samples collected from non-small cell lung cancer patients who had undergone surgical resection. We assigned patients to high and low expression groups and analyzed survival. Cellular morphology, adhesion, proliferation, migration and invasion were examined in human lung cancer cell lines. RESULTS: Among 100 cases, 41 were female, with a median age of 71 years. High expression of integrin alpha 2 in non-small cell lung cancer was associated with lower recurrence-free survival (P = 0.004). Overexpression of integrin alpha 2 in cell lines had no effect on cell proliferation or invasion but resulted in increased cell size (1416 µm2 versus 470 µm2 in H522 cells, P < 0.001; 1822 µm2 versus 1029 µm2 in H661 cells, P = 0.02), adhesion (P < 0.001 in H522 and H661 cells) and migration (gap area filled was 71% versus 36% in H522 cells, P < 0.001; 57% versus 26% in H661 cells, P = 0.001). These changes were suppressed by E7820, an inhibitor of integrin alpha 2. CONCLUSIONS: Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence.

Tumor mutational burden measurement using comprehensive genomic profiling assay.

BACKGROUND: Tumors with a high number of mutations in the genome, or tumor mutational burden, are presumed to be more likely to respond to immune checkpoint inhibitors. However, the optimal method to calculate tumor mutational burden using comprehensive genomic profiling assays is unknown. METHODS: Todai OncoPanel is a dual panel of a deoxyribonucleic acid panel and a ribonucleic acid panel. Todai OncoPanel deoxyribonucleic acid panel version 6 is an improvement over version 3 with increased number of targeted genes and limited targeting of intronic regions. We calculated tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid panel versions 3 and 6 using three different calculation methods: all mutations within the targeted region (target tumor mutational burden), all mutations within the coding region (all coding tumor mutational burden) and non-synonymous mutations (non-synonymous coding tumor mutational burden). We then compared them with whole exosome sequencing tumor mutational burden. In addition, 16 lung cancer patients whose samples were analyzed using Todai OncoPanel deoxyribonucleic acid version 3 were treated with anti-PD-1 or PD-L1 antibody monotherapy. RESULTS: When compared with whole exosome sequencing tumor mutational burden as the standard, tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid version 3 resulted in accuracy of 71% for all three calculation methods. In version 6, accuracy was 96% for target tumor mutational burden and all coding tumor mutational burden and 91% for non-synonymous coding tumor mutational burden. Patients with either partial response or stable disease had higher non-synonymous coding tumor mutational burden (6.7/Mb vs. 1.6/Mb, P = 0.02) and higher PD-L1 expression (40% vs. 3%, P = 0.01) and a trend toward higher target tumor mutational burden (9.2/Mb vs. 2.4/Mb, P = 0.09) compared with patients with progressive disease. CONCLUSIONS: Increase in targeted gene number and limiting intronic regions improved tumor mutational burden measurement by Todai OncoPanel when compared with whole exosome sequencing tumor mutational burden. Target tumor mutational burden may be the method of choice to measure tumor mutational burden.

Lower dose of ethambutol may reduce ocular toxicity without radiological deterioration for Mycobacterium avium complex pulmonary disease.

BACKGROUND: Ethambutol ocular toxicity is a major problem during combination chemotherapy for Mycobacterium avium complex (MAC) pulmonary disease (MAC-PD) due to years-long therapy for MAC. OBJECTIVES: This study aimed to identify the lower dose of daily ethambutol that can reduce ocular toxicity. METHODS: We retrospectively reviewed the medical records of 312 patients who visited The University of Tokyo Hospital between January 2007 and December 2017 for nontuberculous mycobacterial pulmonary disease. Seventy-six patients with MAC-PD who were treated with combination chemotherapy for the first time were analyzed in this study. RESULTS: Ethambutol was discontinued because of visual symptoms in 13 patients (17%), 7 of whom were diagnosed with ethambutol ocular neuropathy. The dose per body weight was significantly higher in patients who developed ocular neuropathy than in those who did not (15.4 mg/kg/d vs. 12.5 mg/kg/d, respectively; p = 0.048). We assigned patients to higher or lower dose groups according to the median dose of 12.5 mg/kg/d. Although ocular neuropathy developed in 6 out of 38 patients in the higher dose group, ocular neuropathy developed in 1 out of 38 patients in the lower dose group (16% vs. 3%, respectively; p = 0.038). The failures of sputum culture conversion and radiological improvement were not significantly different between the two groups (p = 0.638 and 0.305, respectively). Macrolide resistance developed in one patient per group during follow-up (3% per group, p = 0.945). CONCLUSIONS: A lower dose of ethambutol may reduce ocular toxicity without radiological deterioration for pulmonary MAC infection.

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade malignancy, and treatment strategies have not changed for decades. In this study, we searched for novel targets for antibody-drug conjugate (ADC) therapy for SCLC. We identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1 (NRXN1). The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines (SHP77 and NCI-H526). The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines. Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy. Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

Integrin α11 in non-small cell lung cancer is associated with tumor progression and postoperative recurrence.

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11ß1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT-PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.