Abstract 3747: Identification of NSCLC biomarkers underlying quantifiable drug-induced clonal fitness

Lung cancer accounts for nearly 20% of all cancer-related deaths worldwide. Subsets of non-small-cell lung cancer (NSCLC; >80% of all lung cancers) harboring activating epidermal growth factor receptor (EGFR) mutations are highly sensitive to erlotinib, a small-molecule EGFR tyrosine kinase inhibitor. However, clinical responses to erlotinib are variable and limited in duration as all tumors eventually relapse. Clonal heterogeneity is thought to be a major cause of relapse, but it has been difficult to quantify in drug-sensitive cancer cell populations. To overcome this obstacle, we quantify clonal fitness via live-cell imaging as a drug-induced proliferation (DIP) rate that incorporates cell division, death, and quiescence into a single metric. This fitness rate varies across cell types from positive (division prevails) to negative (death prevails) and, unlike traditional IC50 measurements, can effectively discriminate intricate degrees of drug sensitivity. Moreover, in monoclonal sublines isolated naïve-to-drug from NSCLC parental cell lines, erlotinib-treated DIP rates calculated in vitro predict the long-term growth rates (250+ days) of in vivo tumor xenografts. Using global proteomics across a panel of monoclonal sublines, we have characterized networks of biomarkers that act as molecular determinants of phenotypic drug fitness. We have identified unsuspected molecular correlates in the EGFR and AKT pathways and are currently investigating whether they can act as lead targets for small molecule inhibition in combination therapies. Our data indicate that a multi-scale systems approach integrating molecular subtyping with quantifiable clonal fitness can yield insights into clonal heterogeneity and lead to novel strategies to overcome tumor relapse.Note: This abstract was not presented at the meeting.Citation Format: Katherine L. Jameson, Peter L. Frick, Darren R. Tyson, Thomas E. Yankeelov, Vito Quaranta. Identification of NSCLC biomarkers underlying quantifiable drug-induced clonal fitness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3747. doi:10.1158/1538-7445.AM2015-3747

Duke Scholars

Author Darren Tyson Pharmacology & Cancer Biology