Abstract B22: Acyl-CoA synthetase long-chain family member 3 dependent lipid homeostasis is required for mutant KRAS driven lung cancer
Authors: Padanad Mahesh S. , Konstantinidou Georgia , Yang Chendong , Melegari Margherita , Venkateswaran Niranjan , Batten Kimberly , Huffman Kenneth E. , Shay Jerry W. , Minna John D. , DeBerardinis Ralph J. , Scaglioni Pier P. 
Published: May 2016

Lung cancer is the leading cause of cancer related deaths in the USA and worldwide. Lung tumorigenesis is a multistep process that involves several genetic aberrations. Activating mutations of the proto-oncogene KRAS (mutant KRAS) occur in ~30% of the cases of human non-small cell lung cancer (NSCLC), which is associated with aggressive, therapy-resistant disease. Despite the recent discovery of low affinity inhibitors, mutant KRAS is a challenging therapeutic target and there is a dearth of therapeutic options for these tumors. Mutant KRAS not only promotes tumorigenesis but also the survival of established lung cancer, both in mouse models and in certain human NSCLC lines. Therefore, in the absence of clinically-relevant effective inhibitors of mutant KRAS, there has been an intense clinical interest in the development of inhibitors of its downstream effectors. Importantly, mutant KRAS cancer cells undergo oncogene-directed metabolic reprogramming in order to meet the energetic and biosynthetic challenges of cell survival, growth and proliferation. Activation of certain pathways of fatty acid synthesis has been observed in many cancer types including lung cancer. Till date, fatty acid synthase (FASN) has been the candidate for drug development. Unfortunately, the inhibitors against FASN have poor pharmacokinetics and target related toxicity concerns. There is an urgent need for discovery of additional targets that inhibit lipid metabolism specifically in cancer cells that could be exploited for therapeutic gain.

The goal of our study was to identify the cellular networks that mediate the maintenance of mutant KRAS lung cancer which further could be used as high priority therapeutic targets. To this end, we functionally analyzed the transcriptome of transgenic mouse lung tumors manipulated in vivo to undergo mutant Kras extinction, providing isogenic comparisons between mutant KRAS extinguished versus non-extinguished tumors for the discovery of new therapeutic targets.

We determined that mutant KRAS controls tumor metabolism by regulating lipid homeostasis. We found that Acyl-CoA synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrate for lipid synthesis and β-oxidation, is required for the survival of mutant KRAS lung cancer cells. These effects were not due to generalized toxicity, since we did not observe them in immortalized human bronchoalveolar cells and several NSCLC cells expressing wild type KRAS and in Acsl3 null mouse embryonic fibroblasts. We confirmed that ACSL3 is a mutant KRAS responsive gene expressed in the respiratory epithelium, in lung cancer cells and in primary human cancers. With mechanistic experiments we determined that mutant KRAS stimulates, in an ACSL3-dependent manner, the uptake and retention of fatty acids by lung cancer cells as well as their β-oxidation. As predicted by these experiments, ACSL3 is essential for the ability of mutant KRAS human lung cancer cells to form colonies in soft agar or to establish xenografts in immunocompromised mice. In addition, our preliminary results shows reduced tumor size and tumor burden in KrasG12D;Acsl3-/- mice. The detailed characterization of these mice is currently in progress.

Our data demonstrate that mutant KRAS reprograms lipid homeostasis in lung cancer, establishing a cancer specific metabolic vulnerability. Thus, ACSL3 could be a viable therapeutic target for NSCLC driven by mutant KRAS.

Citation Format: Mahesh S. Padanad, Georgia Konstantinidou, Chendong Yang, Margherita Melegari, Niranjan Venkateswaran, Kimberly Batten, Kenneth E. Huffman, Jerry W. Shay, John D. Minna, Ralph J. DeBerardinis, Pier P. Scaglioni. Acyl-CoA synthetase long-chain family member 3 dependent lipid homeostasis is required for mutant KRAS driven lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B22.