Program Official

Principal Investigator

Kwon-Sik
Park
Awardee Organization

University Of Virginia
United States

Fiscal Year
2022
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Targeting BCAT1 and branched-chain amino acid metabolism for the detection and prevention of SCLC

The high mortality of small cell lung cancer (SCLC) is largely due to its invariable resistance to current cytotoxic therapies. Chemoprevention has been considered as an alternative to existing therapeutics on the basis of long tumor latency and the well-defined high-risk population (e.g. smokers). Identification of tractable targets for prevention and early detection requires an understanding of molecular changes underlying earlystage tumor development. We found that enhanced ribosome biogenesis and protein synthesis are critical for MYC family-driven transformation of precancerous precursors (preSC) into fully tumorigenic cells. Both human and mouse SCLC cells are extremely sensitive to a specific inhibitor of ribosome biogenesis that has also been shown to reduce tumor growth in a genetically engineered mouse model. Analysis of the MYC-driven oncogenic gene signature revealed branched-chain aminotransferase 1 (BCAT1) as a potential modulator of both metabolic adaptation and related stress response to promote cellular homeostasis. BCAT1 is an enzyme that catalyzes transfer of the α-amino nitrogen from branched-chain amino acids (BCAAs including leucine) to α-ketoglutarate to produce branched-chain α-keto acids (BCKAs) and glutamate. This enzyme routes BCAAs into multiple metabolite pools for biosynthesis and regulates levels of BCAAs, specifically leucine, that stimulate protein synthesis by acting as indicators of nutrient availability. BCAT1 has recently been implicated in multiple types of cancers, including glioblastoma and mouse Kras/p53-driven lung adenocarcinoma. In this application, we will test the hypotheses that enhanced BCAT1 promotes SCLC development by controlling protein synthesis and stress response, and that altered levels of BCAA metabolites inform early BCAT1dependent SCLC development. To test these hypotheses, we propose the following Aims. Aim 1: To determine the necessity of BCAT1 for SCLC development, we will evaluate the tumor suppressive effects of knocking out Bcat1 and examine the effects of pharmacological inhibition of BCAT1 on SCLC development and long-term survival in vivo. Aim 2: To determine the role of BCAT1 in protein synthesis and stress response during SCLC development, we will manipulate BCAT1 and determine the resulting impact on biochemical interactions among related proteins and pathways that influence proliferation and survival of L-Myc-induced transforming cells, a model of early stage SCLC. We will also determine the significance of BCAA metabolism in tumor development in vivo by setting up variable conditions that mimic different outcomes of the metabolic reaction using a BCAA-defined diet. Aim 3: To test alterations in BCAA metabolites as biomarkers for BCAT1dependent SCLC development, we will monitor changes in plasma BCAA and BCKA levels during SCLC development in vivo and examine the clinical correlation of plasma levels of these metabolites with a SCLC diagnosis. The expected outcome of this proposal will provide critical insights into novel strategies for targeted prevention using minimally invasive detection methods and intervention using low-toxicity drugs or nutrition.

Publications

  • Kim KB, Dunn CT, Park KS. Recent progress in mapping the emerging landscape of the small-cell lung cancer genome. Experimental & molecular medicine. 2019 Dec 12;51(12):1-13. PMID: 31827074
  • Ko JH, Olona A, Papathanassiu AE, Buang N, Park KS, Costa ASH, Mauro C, Frezza C, Behmoaras J. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages. Journal of cell science. 2020 Nov 27;133. (22). PMID: 33148611
  • Kim KB, Kabra A, Kim DW, Xue Y, Huang Y, Hou PC, Zhou Y, Miranda LJ, Park JI, Shi X, Bender TP, Bushweller JH, Park KS. KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer. Science advances. 2022 Feb 18;8(7):eabl4618. Epub 2022 Feb 16. PMID: 35171684
  • Kirk NA, Kim KB, Park KS. Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer. Experimental & molecular medicine. 2022 Dec;54(12):2118-2127. Epub 2022 Dec 12. PMID: 36509828
  • Schaff DL, Singh S, Kim KB, Sutcliffe MD, Park KS, Janes KA. Fragmentation of Small-Cell Lung Cancer Regulatory States in Heterotypic Microenvironments. Cancer research. 2021 Apr 1;81(7):1853-1867. Epub 2021 Feb 2. PMID: 33531375
  • Kim KB, Kim DW, Kim Y, Tang J, Kirk N, Gan Y, Kim B, Fang B, Park JL, Zheng Y, Park KS. WNT5A-RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer. Cancer research. 2022 Nov 15;82(22):4219-4233. PMID: 36102736
  • Pereira M, Ko JH, Logan J, Protheroe H, Kim KB, Tan ALM, Croucher PI, Park KS, Rotival M, Petretto E, Bassett JD, Williams GR, Behmoaras J. A trans-eQTL network regulates osteoclast multinucleation and bone mass. eLife. 2020 Jun 19;9. PMID: 32553114
  • Kim KB, Kim Y, Rivard CJ, Kim DW, Park KS. FGFR1 Is Critical for RBL2 Loss-Driven Tumor Development and Requires PLCG1 Activation for Continued Growth of Small Cell Lung Cancer. Cancer research. 2020 Nov 15;80(22):5051-5062. Epub 2020 Sep 24. PMID: 32973083
  • Jia D, Augert A, Kim DW, Eastwood E, Wu N, Ibrahim AH, Kim KB, Dunn CT, Pillai SPS, Gazdar AF, Bolouri H, Park KS, MacPherson D. Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition. Cancer discovery. 2018 Nov;8(11):1422-1437. Epub 2018 Sep 4. PMID: 30181244