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Title page for ETD etd-03232015-094458


Type of Document Dissertation
Author Amato, Katherine Renee
URN etd-03232015-094458
Title Targeting the EPHA2 receptor tyrosine kinase in KRAS and EGFR mutant lung cancer
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Pierre Massion Committee Chair
Deborah Lannigan Committee Member
Jin Chen Committee Member
Rebecca Cook Committee Member
Keywords
  • TKI
  • EPH
  • KRAS
  • EGFR
Date of Defense 2015-03-06
Availability unrestricted
Abstract
Lung cancer remains the leading cause of cancer related deaths in the United States despite a significant number of advancements in the molecular diagnosis and treatment of this disease. Recent genome wide expression analyses of human lung cancer has identified a number of receptor tyrosine kinases (RTKs) as overexpressed and potentially representing molecular drivers of lung cancer. Among these RTKs identified was EPHA2, which is highly expressed in lung cancer correlating to poor clinical outcomes. The role of EPHA2 in lung cancer, specifically in distinct molecular subtypes, is largely unknown. In this study, we dissected the role of EPHA2 in a variety of molecular subtypes of lung cancer and discovered that KRAS and EGFR(T790M) mutant lung cancers were most vulnerable to inhibition of EPHA2 by either genetic or pharmacological methods. We demonstrated functional evidence in vivo that the EPHA2 receptor is required for tumor growth and survival in both Kras(G12D) and EGFR(L858R+T790M) transgenic mouse models. We also showed that in lung cancer EPHA2 controls cell viability through a PI3K/mTOR dependent mechanism regulating apoptosis. Additionally, we identified a novel, ATP competitive EPHA2 RTK inhibitor, ALW-II-41-27, which was capable of inhibiting KRAS and EGFR mutant lung cancer cell viability both in vitro and in vivo. Overall these findings provide genetic, functional, mechanistic, and pharmacologic evidence that EPHA2 promotes the progression and survival of lung tumors. In addition, these findings provide rationale for the development of EPHA2 targeted therapeutics for clinical use.
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