Summer Research Description: Despite efforts, lung cancer remains the most common cause of cancer-related death in the world. New strategies for treatment focus on targeted therapy at the cellular level. Irregularly expressed tyrosine kinases are of particular interest for their role in cancer cell proliferation. Genomic alterations in the tyrosine kinases, Anaplastic Lymphoma Kinase (ALK) and Epidermal Growth Factor Receptor (EGFR), are found in distinct cohorts of patients with lung cancer. These mutated kinases are therapeutically targetable with orally administered tyrosine kinase inhibitors (TKIs), several of which have already gained approval from the Food and Drug Administration given their dramatic response rates and significantly improved clinical outcomes in lung cancer patients. Unfortunately, acquired resistance to TKI therapy has become another obstacle to overcome. This study investigates the effectiveness of novel targeted therapies as well as rational combination therapies in ALK-mutated and EGFR-mutated lung cancer cell lines. For ALK-mutated cells, we evaluated the efficacy of several 2nd generation ALK TKIs to ascertain if more potent ‘on-target’ ALK inhibition was able to prolong initial response time and also overcome resistance to the 1stgeneration ALK TKI, crizotinib. For EGFR-mutated cells, we evaluated the efficacy of 3rd generation mutant specific EGFR TKIs alone or in combination with 1st generation wild-type specific EGFR TKIs to prolong initial response time and overcome resistance. In addition, this investigation explores the prospect of a novel therapy targeting the DNA methyltransferase, EZH2, which is over-expressed in a wide array of tumors. Future investigations hope to show that inhibition of this transcriptional repressor may help trigger apoptotic pathways in lung cancer cells. Overall, our studies are aimed at developing novel therapeutic strategies which delay or overcome drug resistance with the ultimate goal of providing the most effective treatments for patients with lung cancer.