Awardees:

Title: Exploiting ferroptosis to eliminate colorectal cancer cells with KRAS mutations

Ferroptosis is an iron-dependent form of regulated necrotic cell death triggered by oxidative degradation of lipids in membrane bilayers and subsequent irreparable damages to the plasma membrane. This fatal chain of reactions occurs when the downregulation of key metabolic determinants creates an imbalance between the production of free radicals and antioxidants. Notably, lipid peroxidation is observed following:
i) the depletion of intracellular glutathione (GSH) via the inhibition of cell membrane transporters such as the cystine/glutamate transporter;
ii) the blockade of intracellular antioxidant enzymes (such as glutathione peroxidase GPX4);
iii) increased labile iron pools.

Interestingly, whereas the contribution of ferroptosis in development and physiological homeostasis remain largely obscure, induction of ferroptosis has been convincingly established as a potentially important strategy to improve cancer treatment. In particular, colorectal cancer (CRC) cells harbouring oncogenic KRAS mutations are exquisitely sensitive to ferroptotic activators such erastin and RAS-selective lethal 3 (RSL3). CRC is the third most deadly cancer and the second leading cause of global cancer mortality worldwide. Despite the development of diagnostic and therapeutic strategies, most CRC patients are diagnosed at an advanced stage and CRC remains one of the most severe human cancers due to resistance to treatment. Hence, this project will aim at understanding the basic mechanism underpinning CRC cells sensitivity to ferroptosis through KRAS-mediated metabolic reprogramming in order to establish novel therapeutic opportunities to treat incurable CRC.