Fellowship: Madeline Krentz: Gene Expression Profiles Reveal Alternative Targets of Therapeutic Intervention for the Treatment of Drug-Resistant Non-SmallCell Lung Cancers

More than 80% of lung cancer patients die from drug-resistant, metastatic disease. This is largely due to the late stage of diagnosis and the poor treatment outcomes common in these advanced stage cancers. Our focus is to identify new drug targets and alternative therapeutic strategies to improve outcomes for this majority of lung cancer patients who glean little, if any, benefit from conventional lung cancer therapies. Erlotinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor approved for the treatment of locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after the failure of at least one prior chemotherapy regimen. However, current means of predicting response using single biomarkers have been only modest at best. As a solution, this lab hypothesized that clinical predictive capacity could be improved by use of multivariate biomarker expression patterns in cells with divergent responses to erlotinib. A microarray analysis of known erlotinib-resistant and -sensitive NSCLC cell lines identified a 13-gene microRNA (miRNA) signature of response to erlotinib. A bioinformatic analysis of the 13 miRNA genes revealed a functional convergence on the TGFâ signaling pathway, suggesting a relationship between the TGFâ and EGFR signaling pathways. We hypothesize that TGFâ signaling participates in the development and maintenance of erlotinib-resistance and –sensitivity. The cross-talk between the two signaling pathways represents a unique opportunity for development of novel therapeutic approaches and for identification of novel therapeutic targets to combat drug resistance in NSCLC.