https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(20)30320-X

Mitochondrial Metabolism as a Target for Cancer Therapy.

Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.

/pdf/suppression-of-the-slc7a11-glutathione-axis-causes-synthetic-55gvusfwyh.pdf

Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

https://estudogeral.sib.uc.pt/bitstream/10316/84850/1/34_Bajzikova2018_CellMetabolism.pdf

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.

Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to support nucleic acid and protein synthesis along with energy preservation, signaling activity, glycosylation mechanisms, and cytoskeletal function. Both oncogenes and tumor suppressors have recently been identified as key molecular determinants for de novo nucleotide synthesis that contribute to the maintenance of homeostasis and the proliferation of cancer cells. Inactivation of tumor suppressors such as TP53 and LKB1 and hyperactivation of the mTOR pathway and of oncogenes such as MYC, RAS, and AKT have been shown to fuel nucleotide synthesis in tumor cells. The molecular mechanisms by which these signaling hubs influence metabolism, especially the metabolic pathways for nucleotide synthesis, continue to emerge. Here, we focus on the current understanding of the molecular mechanisms by which oncogenes and tumor suppressors modulate nucleotide synthesis in cancer cells and, based on these insights, discuss potential strategies to target cancer cell proliferation.

https://www.mdpi.com/2072-6694/11/5/688/pdf

Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides.

Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer.

Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Activating KRAS mutations are oncogenic and prevalent in multiple tumor types, being found in as high as 90% of pancreatic carcinomas and 50% of colorectal carcinomas. In spite of its attractiveness for therapeutic intervention to date no KRAS-targeted drug therapies have been approved. Most of the reported mutant KRAS directed cellular screening efforts utilize 2-dimensional assays. Because mutant KRAS driven tumor cell lines are much more strongly dependent on activated K-Ras signaling for anchorage independent growth relative to growth when anchored to plastic, we report herein a screening strategy that leverages a 3-dimensional clonogenic growth assay in soft agar. We have performed a multi-cell line parallel phenotypic high throughput screen with our proprietary compound collection to identify pathways, targets and chemical matter with selective anti-tumor activity in mutant KRAS dependent cell lines - a Synthetic Lethal approach.

Our strategy has led to the identification of several chemical classes that inhibit the growth of multiple mutant KRAS cell lines of pancreatic and colorectal carcinoma origin, while sparing multiple wild-type KRAS cancer cell lines. Studies to elucidate their molecular mechanisms of action are underway.

Citation Format: Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Daniel Simard, Maria Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Hui Cao, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Francisco Adrian, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron J. Morris. Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2013-2243

Abstract 2243: Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach.

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Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers

Abstract 2243: Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach.