Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

PURPOSE: Skin allergies through type 1 and 4 hypersensitivity reactions are the most frequent manifestations of drug allergies. We had previously experienced a case of a nurse with cefotiam-induced contact urticaria syndrome. To aid in preventing the progression of drug-induced allergic disease in nurses, we conducted a survey of tertiary hospital nurses who were likely to have been exposed professionally to antibiotics. METHODS: All 539 staff nurses at a tertiary hospital were asked to respond to a questionnaire regarding antibiotic exposure. Of the 457 nurses (84.8%) who responded, 427 (79.2%) received a physical examination of the hands and 318 (59.0%) received skin prick tests with the beta-lactam antibiotics cefotiam, cefoperazone, ceftizoxime, flomoxef, piperacillin and penicillin G. RESULTS: A positive response to at least one of the antibiotics occurred in 8 (2.6%) of the 311 subjects included in the analysis and stages 1 and 2 contact urticaria syndrome were observed in 38 (8.9%) and 3 (0.7%) of 427 nurses, respectively. The frequencies of a positive antibiotic skin test (6.9 versus 1.3%, chi-square=7.15, P=0.018), stage 1 contact urticaria syndrome (14.4 versus 7.4%, chi-square=4.33, P=0.038) and drug allergy (15.3 versus 3.6%, chi-square=18.28, P=0.000) were higher in subjects with a positive skin allergy history than in those without. Allergic rhinitis (P=0.02, OR=3.86, CI=1.23-12.06), night cough (P=0.04, OR=3.12, CI=1.03-9.41) and food allergy (P=0.00, OR=9.90, CI=3.38-29.98) were significant risk factors for drug allergy. CONCLUSIONS: Antibiotic sensitization and drug allergy occurred more frequently in nurses with a positive skin allergy history. Atopy may be an important risk factor for drug allergy.
Anti-Bacterial Agents ; Cefoperazone ; Cefotiam ; Ceftizoxime ; Cephalosporins ; Cough ; Drug Hypersensitivity ; Food Hypersensitivity ; Hand ; Hypersensitivity ; Penicillin G ; Physical Examination ; Piperacillin ; Rhinitis ; Rhinitis, Allergic, Perennial ; Risk Factors ; Skin ; Skin Tests ; Tertiary Care Centers ; Urticaria ; Surveys and Questionnaires

PURPOSE: Skin allergies through type 1 and 4 hypersensitivity reactions are the most frequent manifestations of drug allergies. We had previously experienced a case of a nurse with cefotiam-induced contact urticaria syndrome. To aid in preventing the progression of drug-induced allergic disease in nurses, we conducted a survey of tertiary hospital nurses who were likely to have been exposed professionally to antibiotics. METHODS: All 539 staff nurses at a tertiary hospital were asked to respond to a questionnaire regarding antibiotic exposure. Of the 457 nurses (84.8%) who responded, 427 (79.2%) received a physical examination of the hands and 318 (59.0%) received skin prick tests with the beta-lactam antibiotics cefotiam, cefoperazone, ceftizoxime, flomoxef, piperacillin and penicillin G. RESULTS: A positive response to at least one of the antibiotics occurred in 8 (2.6%) of the 311 subjects included in the analysis and stages 1 and 2 contact urticaria syndrome were observed in 38 (8.9%) and 3 (0.7%) of 427 nurses, respectively. The frequencies of a positive antibiotic skin test (6.9 versus 1.3%, chi-square=7.15, P=0.018), stage 1 contact urticaria syndrome (14.4 versus 7.4%, chi-square=4.33, P=0.038) and drug allergy (15.3 versus 3.6%, chi-square=18.28, P=0.000) were higher in subjects with a positive skin allergy history than in those without. Allergic rhinitis (P=0.02, OR=3.86, CI=1.23-12.06), night cough (P=0.04, OR=3.12, CI=1.03-9.41) and food allergy (P=0.00, OR=9.90, CI=3.38-29.98) were significant risk factors for drug allergy. CONCLUSIONS: Antibiotic sensitization and drug allergy occurred more frequently in nurses with a positive skin allergy history. Atopy may be an important risk factor for drug allergy.
Anti-Bacterial Agents ; Cefoperazone ; Cefotiam ; Ceftizoxime ; Cephalosporins ; Cough ; Drug Hypersensitivity ; Food Hypersensitivity ; Hand ; Hypersensitivity ; Penicillin G ; Physical Examination ; Piperacillin ; Rhinitis ; Rhinitis, Allergic, Perennial ; Risk Factors ; Skin ; Skin Tests ; Tertiary Care Centers ; Urticaria ; Surveys and Questionnaires

Purpose: Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation–positive non–small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea. Materials and Methods: Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints. Results: A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects. Conclusion Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation–positive in Korean patients with no new safety signals.