Non-small cell lung cancer (NSCLC) remains the most commonly diagnosed malignancy and leading cause of cancer related deaths worldwide; yet there is a fundamental gap in understanding the biology of lung cancer formation. Sequencing data of human NSCLC revealed KRAS is one of the most frequent oncogene aberrations in lung adenocarcinoma patients. We have recently generated a novel mouse model of NSCLC driven by an oncogenic mutation in KRASG12D and concurrent genetic deletion of MST1/2. When mice express mutant KRASG12D alone in alveolar epithelial type II cells (AECII), we observe focal lung adenomas and neoplasia; however, when MST1/2 are genetically deleted in combination with KRASG12D, we observe aggressive lung adenocarcinoma. To define early mechanisms by which loss of MST1/2 accelerates KRASG12D driven NSCLC, we performed a proteomics screen prior to observing NSCLC on lung tissue from our mouse models. Our proteomic analysis revealed pyruvate kinase M2 (PKM2), a rate-limiting enzyme during glycolysis that catalyzes the production of pyruvate and ATP, is highly expressed, even before the onset of tumors. As improved targeted therapies and diagnostic tests have the potential to significantly improve patient outcomes, we now want to study the mechanism by which loss of MST1/2 promotes increased PKM2. Our central hypothesis is reduced expression of MST1/2 is important in the development of NSCLC. We predict loss of MST1/2 promotes increased abundance and nuclear localization of PKM2, to promote altered glucose metabolism and survival. We plan to test our overall hypothesis by pursuing the following specific aims:
Aim 1 : To test the hypothesis that MST1 restrains aerobic glucose metabolism in KRAS mutant epithelial cells. Rationale: We have generated new preliminary data that inhibition of MST1 increases PKM2 and pPKM2 in cultured lung epithelial cells expressing KRASG12D. We also have new data using Seahorse assays that inhibition of MST1 significantly increases oxygen consumption rate and ATP production in cultured human NSCLC. We now want to conduct in vivo and in vitro metabolomic analysis to characterize MST1-dependent metabolic programs in human and mouse models driven by mutant KRAS.
Aim 2 : To test the hypothesis that YAP/TAZ are required for mutant KRAS induction of PKM2. Rationale: We have generated preliminary data using transient knockdown of PKM2 which revealed decreased metabolic activity and proliferation in human NSCLC. In this aim, we will determine what molecular events are causing posttranslational modifications on PKM2 to promote dimerization and nuclear translocation. Using genetic knockdown, we will determine if YAP or TAZ are required for increased expression of PKM2. We will use Seahorse analysis and mass spec to study PKM2 modifications and other metabolic alterations in YAP or TAZ deficient cells. In addition, in response to reviewer comments, we are crossing PKM2fl/fl mice into our genetic model to define the requirement for PKM2 in adenoma-adenocarcinoma development in vivo.

Public Health Relevance

/PUBLIC HEALTH RELEVANCE The proposed research is relevant to public health because the understanding how signaling pathways cooperate with oncogenic mutations in KRAS in lung epithelial cells will aid in understanding the biology of lung cancer develpoment including defining better therapeutic options for patients. Thus, the proposed research is relevant to the NIH?s mission that pertains to developing fundamental knowledge that will enhance health, lengthen life and reduce illness.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Tumor Cell Biology Study Section (TCB)
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Willis, Kristine Amalee
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University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
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