Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells.

Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin ß1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.

Phase II trial of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for untreated non-squamous non-small-cell lung cancer.

PURPOSE: We conducted a phase II trial to evaluate the efficacy and safety of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Patients with advanced or recurrent untreated non-squamous NSCLC received split-dose cisplatin (40 mg/m2, days 1 and 8) plus pemetrexed (500 mg/m2, day 1) tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity. The primary endpoint was the 1-year survival rate. The secondary endpoints were progression-free survival (PFS), overall survival (OS), response in induction phase, and safety. RESULTS: From February 2012 to September 2014, 53 assessable patients were enrolled in this study. Thirty-eight (71.7%) patients completed induction therapy, while 35 (66.0%) received maintenance therapy. The 1-year survival rate was 67.7%. The median PFS and OS were 5.3 and 18.6 months, respectively. The response rate and disease control rate (DCR) during the induction phase were 37.7 and 86.8%, respectively. Eight patients (15.1%) discontinued the therapy due to adverse events (AEs) during the induction phase, but both hematological and non-hematological AEs were infrequent. CONCLUSIONS: Treatment with induction chemotherapy of pemetrexed plus split-dose cisplatin showed a promising 1-year survival rate, DCR, and transition rate into maintenance phase. This regimen is feasible and well-tolerated. A phase III study comparing this regimen with conventional tri-weekly regimen is warranted.

Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer.

PURPOSE: To assess the efficacy and toxicity of S-1 and bevacizumab combination therapy for patients previously treated for advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1-14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% [95% confidence interval (CI) 1.8-21.3%], and the disease control rate (DCR) was 80% (95% CI 62.7-90.5%). Median PFS was 4.8 months (95% CI 2.7-6.4 months], and median OS was 13.8 months (95% CI 8.4 months-not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%). CONCLUSION: The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.