Nicotine Induces Resistance to Erlotinib Therapy in Non-Small-Cell Lung Cancer Cells Treated with Serum from Human Patients

Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs by treating cancer cell lines with erlotinib, afatinib, or osimertinib, and serum collected from smokers within 30 min of smoking and that from a non-smoker as a control. We also assessed erlotinib resistance by treating PC9 cells exposed to serum from a smoker or a non-smoker, or serum from an erlotinib user. Treatment of the cancer cell lines with serum from smokers induced significant erlotinib resistance, compared with the control (p < 0.05). Furthermore, serum samples with a high concentration of cotinine (a nicotine exposure indicator) demonstrated stronger erlotinib resistance than those with low concentrations. Similar to the observations with erlotinib treatment of cell lines, the analysis of serum from erlotinib users revealed that smokers demonstrated significantly reduced sensitivity to erlotinib (p < 0.001). In conclusion, our present results support the hypothesis that smoking contributes to resistance to erlotinib therapy in non-small-cell lung cancer.

The frequency of EGFR And KRAS mutations in the Turkish population with non-small cell lung cancer and their response to erlotinib therapy

In this study, profiles of epidermal growth factor receptor (EGFR) and Kirsten ras sarcoma (KRAS) mutations and response to erlotinib therapy have been investigated in patients with non-small cell lung cancer (NSCLC). DNA from 300 patients with NSCLC was extracted from paraf-fin-embedded tissues. After the extracted DNA was sequenced by pyrosequencing method, a total of 97 (32.0%) patients out of 300 were detected to carry an EGFR mutation and 75 (25.0%) patients out of 300 carried a KRAS mutation; 20 (6.6%) patients were detected to carry both of EGFR and KRAS mutations. The EGFR mutations were found to be statistically significant in female patients (48.0 women vs. 28.0% men, non smokers (49.0 vs. 26.0%) and adenocarcinoma (37.8 vs. squamous 26.8%). The overall rate of survival in patients receiving erlotinib therapy than in patients who did not. In patients without the KRAS mutation, the median overall survival rate was 161 ± 30 weeks with erlotinib therapy and 90 ± 13 weeks in patients without erlotinib therapy. In patients having KRAS mutation, the median overall survival was 98 ± 16 weeks with erlotinib therapy and 34 ± 16 weeks with no erlotinib therapy. In our study, we once again demonstrated that the presence of these mutations affected response to erlotinib therapy. The KRAS mutations negatively affected survival rate with and without erlotinib therapy.