SPECIFIC AIMS The purpose of UCaTS Project 2 is to target clinically important genomic markers of early resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC), to develop quantitative models of Receptor Tyrosine Kinase (RTK)-driven signaling pathways under inhibition, and to explore the role race, ethnicity and genetic ancestry has in predicting baseline EGFR signaling and EGFR-TKI treatment response. EGFR-mutant NSCLC comprises a substantial subset of lung adenocarcinoma (15% in Western/White populations) and occurs with a higher frequency in Asian Americans, Native Hawaiians, Pacific Islanders (AANHPI ~50%), and Latinos (~38%). EGFR mutations show strong associations with smoking status, gender, race/ethnicity, and genetic ancestry. Women of AANHPI and Latino race/ethnicity have, compared to non-Latino Whites (NLW), lower smoking rates and higher frequency of EGFR mutant tumors. Interestingly, a recent study showed that high Indigenous American Ancestry (which is closely associated with Asian ancestry) confers a higher risk of developing EGFR-mutant lung cancer in Latinos. This suggests that somatic EGFR mutations have close associations of biological and non-biological aspects associated with race/ethnicity or ancestry. Through this research, we will develop novel therapeutic strategies with combinations of FDA approved and NCI-CTEP drugs to translate into NCI-sponsored clinical trials overcoming EGFR-TKI resistance mechanisms associated in EGFR-mutant NSCLC. We will also assess whether race/ethnicity and genetic ancestry impacts EGFR signaling and influences responses to EGFR inhibition. Patient-derived xenografts (PDXs) have been broadly used in lung cancer research and drug development. We have extensive experience in establishing PDXs and conducting PDX-based research. Through the Jackson Laboratory (JAX), UCSF and UT Southwestern collaborations, we established and characterized over 200 lung cancer PDXs in which 25 have EGFR-activating mutations and we have identified an additional 10 EGFR-mutant lung cancer models in PDXnet. We anticipate that UCaTS will generate at least 25 additional EGFR-mutant PDXs. We have performed detailed histopathological and genomic characterization on many of these PDXs focused on oncogene driven NSCLC where we identified multiple putative resistance mechanisms that mediate early resistance to current EGFR-targeted therapeutic approaches in these models. We have also shown that EGFR-mutant PDXs can potentially be used to optimize treatment combinations to overcome EGFR-TKI resistance and to identify the most efficacious drugs or drug combinations including FDA approved and NCI- CTEP agents. We will use a high-content live-cell imaging platform to analyze intracellular EGFR signaling, which provides a high-resolution assessment of cellular adaptation to inhibition. The work for this project arises out of our current research, which will be used to address th...