Association of the EGFR-TKI or cytotoxic chemotherapy efficacy with NF-кB and transglutaminase 2 expression level in non-small cell lung cancer

Abstract

Background: Transglutaminase 2 (TG2) is a cross-linking enzyme that is involved in drug resistance and the constitutive activation of nuclear factorкB (NF-кB), a proinflammatory transcription factor. We investigated the association between the clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy and the expression of TG2 and NF-кB in non-small cell lung cancer (NSCLC).Patients and methods: TG2 and NF-кB expression was immunohistochemically studied in 120 patients with NSCLC who underwent curative resection. Kaplan-Meier survival analyses and Cox regression analyses were used to estimate the association between TG2 and NF-кB expression and the clinical efficacy of chemotherapy and EGFR-TKI.Results: The median age of the patients was 64 years (range, 41-84 years). One hundred two cases (85%) had adenocarcinoma, and 18 cases (15%) had other histologies. Eighty eight patients received adjuvant chemotherapy, 28 patients received platinum-based doublet chemotherapy as palliative therapy, and 29 patients received EGFR-TKI. Twenty-five of the patients were current smokers, 16 were former smokers, and 79 were never smokers. Fifty-five patients had an activating EGFR mutation, such as exon 19 deletion or L858R mutation. The median TG2 value was 50 (range, 0-300), and the median NF-кB value was 20 (range, 0-240). The score was obtained semiquantitatively by the multiplication of staining intensity and percentage of staining positive tumor cells. The overall response rate (ORR) for platinum-based doublet chemotherapy was 13.8%, and the disease control rate (DCR) was 69%. No patients achieved a complete response (CR), 14.3% achieved a partial response (PR), 57.1% achieved stable disease (SD), and 21.4% experienced progressive disease (PD). The ORR for EGFR-TKI was 24.1%, and the DCR was 58.6% (CR, 3.4%; PR, 20.7%; SD, 34.5%; PD, 34.5%). Among the 88 patients who received adjuvant chemotherapy, disease-free survival (DFS) did not differ between the low- and high-TG2 groups. Among the 28 patients who received palliative platinum-based doublet chemotherapy, progression-free survival (PFS) was longer in the low-TG2 group compared with the high-TG2 group, although this finding was not statistically significant (11.0 months vs. 7.0 months, p = 0.330). Among the patients who received EGFR-TKI (n = 29; seven first-line, 18 second-line, three third-line, and one fourth-line), PFS was significantly longer in the low-TG2 group compared with the high-TG2 group (11.0 months vs. 2.0 months, p = 0.013). In patients with wildtype EGFR (n = 14) treated with EGFR-TKI, PFS was longer in the low-TG2 group (9.0 months vs. 2.0 months, p = 0.013). We generated a small hairpin RNA of TG2 (sh TG2) expressing replication defective adenovirus. The newly engineered adenovirus showed a TG2-suppressing effect and sensitizing effect of gefitinib on cell viability and apoptosis.Conclusion: The present results suggest that TG2 expression might be a predictive factor associated with prolongation of PFS in patients with NSCLC who are treated with EGFR-TKI.