Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers?

Abstract

Ferroptosis has emerged as a new type of programmed cell death that can be harnessed for cancer therapy. The concept of ferroptosis was for the first time proposed in in the early 2000s, as an iron-dependent mode of regulated cell death caused by unrestricted lipid peroxidation (LPO) and subsequent plasma membrane rupture. Since the discovery and characterization of ferroptosis, a wealth of research has improved our understanding of the main pathways regulating this process, leading to both the repurposing and the development of small molecules.However, ferroptosis is still little understood and several aspects remain to be investigated. For instance, it is unclear whether specific oncogenes, cells of origin or tumor niches impose specific susceptibility/resistance to ferroptosis or if there are some ferroptosis-related genes that may be used as bona fide pan-cancer targetable dependencies. In this context, even though RAS-driven cancer cell lines seemed to be selectively sensitive to ferroptosis inducers, subsequent studies have questioned these results, indicating that in some cases mutant RAS is necessary, but not sufficient to induce ferroptosis. In this perspective, based on publicly available genomic screening data and the literature, we discuss the relationship between RAS-mutation and ferroptosis susceptibility in cancer.

PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response

“…However, if the oncogenic K-Ras-dependent enhancement of glutamine utilization is an important cause of the increased sensitivity of MiaPaCa-2 and PANC1 cells to the combined treatment-induced ferroptosis, it needs further experiments. Indeed, as recently described, genes involved in ferroptosis also exert other functions in different cell contexts, and therefore, the role of glutamine in ferroptosis may also be dependent and not dependent on K-Ras status ( 87 ). Therefore, the differences emerging from our study and from other studies possibly reflect the incomplete understanding of how various factors dictate sensitivity to ferroptosis.…”

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

“…This is the case in KRAS-mutant lung cancers, where SREBP1/FASN-driven de novo lipogenesis is used to limit the amount of PUFAs incorporated into membrane phospholipids, thereby averting lipid peroxidation and ferroptosis. KRAS-driven cancers, but not wild-type KRAS or EGFR-mutants, appear to use endogenous FA biogenesis to survive the oxidative stress of some oxygen-and PUFA-rich microenvironmental conditions, such as the lung [365,366]. In this regard, TVB-3664 has been reported to specifically induce ferroptosis in KRAS-mutant lung cancer models [367].…”

Ferroptosis: Frenemy of Radiotherapy

“…Soon after, additional compounds inducing ferroptosis were discovered, like RAS-selective ligand 3 (RSL3) [11]. However, there is still considerable controversy regarding the relationship between cell mutational status and ferroptosis sensitivity [12]. An important hallmark in ferroptosis research was the discovery of the inhibiting ability of iron-chelating agents, revealing the pivotal role of iron metabolism [11].…”