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Title page for ETD etd-10292013-131538


Type of Document Dissertation
Author Kaufman, Jacob Marcus
Author's Email Address jacob.m.kaufman@vanderbilt.edu
URN etd-10292013-131538
Title LKB1 loss induces characteristic pathway activation in human tumors and confers sensitivity to MEK inhibition associated with attenuated PI3K-AKT-FOXO3 signaling
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
William Pao Committee Chair
Alissa Weaver Committee Member
David Carbone Committee Member
Ethan Lee Committee Member
Pierre Massion Committee Member
Keywords
  • MEK inhibition
  • LKB1
  • lung cancer
Date of Defense 2013-09-23
Availability unrestricted
Abstract
Inactivation of STK11/LKB1 is one of the most common genetic events in lung cancer, and understanding the cellular phenotypes and molecular pathways altered as a consequence will aid the development of therapeutic strategies targeting LKB1-deficient cancers. We report the comprehensive analysis of gene and protein expression patterns associated with LKB1 loss in lung adenocarcinomas, through which we identify hallmarks of altered tumor metabolism and downregulation of the PI3K/AKT pathway. Significant differences are observed between human tumors and those derived from a genetically engineered mouse model of LKB1 loss. A 16-gene signature is predictive of both mutational and non-mutational LKB1 loss in human tumors. Cell lines expressing this signature show increased sensitivity to MEK inhibition, independent of mutations in RAS and RAF family members. Restoration of LKB1 in lung cancer cell lines downregulates the gene expression pattern, attenuates FOXO3, and induces resistance to MEK inhibition. These findings identify characteristic phenotypic features of LKB1-deficient tumors and identify LKB1 loss as a novel determinant of MEK sensitivity.
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