De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer

Anju Singh, Christian Ruiz, Kavita Bhalla, John A. Haley, Qing Kay Li, George Acquaah-Mensah, Emily Montal, Kuladeep R. Sudini, Ferdinandos Skoulidis, Ignacio I. Wistuba, Vassiliki Papadimitrakopoulou, John V. Heymach, Laszlo G. Boros, Edward Gabrielson, Julian Carretero, Kwok Kin Wong, John D. Haley, Shyam Biswal, Geoffrey D. Girnun

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the KrasLSL-G12D lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo. The importance of fatty acid synthesis in Kras-induced tumorigenesis was evident by decreased tumor formation in KrasLSL-G12D mice after treatment with a fatty acid synthesis inhibitor. Importantly, with gain and loss of function models of mutant Kras, we demonstrate that mutant Kras potentiates the growth inhibitory effects of several fatty acid synthesis inhibitors. These studies highlight the potential to target mutant Kras tumors by taking advantage of the lipogenic phenotype induced by mutant Kras.

Original languageEnglish (US)
Pages (from-to)7018-7027
Number of pages10
JournalFASEB Journal
Volume32
Issue number12
DOIs
StatePublished - Dec 2018

Keywords

  • Cancer metabolism
  • NSCLC
  • Warburg Effect

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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