High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer.

BACKGROUND: Prior studies highlighted cyclin D1 as a key biomarker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This study builds on prior work by examining the roles of cyclin D1, cyclin D3, and cyclin E in mediating erlotinib sensitivity or resistance. METHODS: Expression plasmids for G1 cyclins were independently transfected into NIH 3T3 cells and effects on erlotinib sensitivity were examined. The expression profiles of G1 cyclins were compared in erlotinib-sensitive and erlotinib-resistant lung cancer cell lines. A549 and H358 cells were treated with erlotinib and changes in cyclin protein expression were assessed. Cyclin D3 immunohistochemical staining was measured in biopsy tissues obtained from patients before and after treatment with erlotinib. Erlotinib-sensitive lung cancer cells were transfected with cyclin D3 and changes in erlotinib sensitivity were examined. RESULTS: Individual transfection of cyclin D1, cyclin D3, and cyclin E expression plasmids each significantly reduced erlotinib sensitivity in NIH-3T3 cells. The erlotinib-resistant A549 cell line expressed high basal levels of cyclin D3 mRNA and protein. Comparison of tumor biopsies obtained from patients before and after treatment with erlotinib indicated an increase in the percentage of cancer cells expressing cyclin D3 following treatment with erlotinib (P=.02). Transfection of cyclin D3 into an erlotinib-sensitive lung cancer cell line inhibited erlotinib-induced signaling changes and reduced the growth-suppressive effects of erlotinib. CONCLUSIONS: High expression of cyclin D3 confers resistance to erlotinib in vitro and in vivo. Cyclin D3 immunohistochemical staining warrants investigation as a biomarker for predicting erlotinib resistance.

Effects of continued tobacco use during treatment of lung cancer.

Lung carcinoma is one of the most common cancers diagnosed in the USA. A significant portion of these patients have a history of tobacco use and many are smoking at the time of diagnosis. Despite smoking cessation interventions, many patients continue to smoke even after their diagnosis. Those who are able to quit smoking after their diagnosis still have a high rate of relapse of smoking within the first year. Continued smoking has been found to have multiple negative consequences for these patients including increased toxicity from treatment and decreased effectiveness of therapy. Overall, patients who continue to smoke after their diagnosis have poorer outcomes than those patients who are successfully able to quit and abstain from smoking. Knowing this, physicians should encourage smoking cessation in this patient population. Future studies are needed to help define the best approach for encouraging smoking cessation, taking into account patient characteristics and the stress associated with the lung cancer diagnosis.

Using erlotinib to treat patients with non-small cell lung cancer who continue to smoke.

Erlotinib is active for unselected patients with advanced non-small cell lung cancer. Patients who smoke, however, are less likely to respond and less likely to experience toxicity. These patients rapidly metabolize erlotinib and experience lower drug exposure when treated with standard doses. A recent dose escalation study established 300 mg daily as the recommended Phase II dose in patients who continue to smoke. Pharmacokinetic profiles of erlotinib in current smokers taking 300 mg daily were comparable to non-smokers taking 150 mg daily. Current smokers taking 300 mg daily had a toxicity profile comparable to the toxicity profile for patients in the BR.21 trial. Determining the best strategy for overcoming erlotinib resistance may require understanding both pharmacokinetic and tumor-specific resistance mechanisms. Individually, the selection and dosing of erlotinib for the treatment of lung cancer patients who continue to smoke is a clinical challenge.