Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Abstract

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

Prostate Cancer Progression: as a Matter of Fats

“…Since SFAs are more resistant to lipid peroxidation, metastatic PCa cells with SFA-enriched membranes would be most likely less susceptible to oxidative stress-induced ferroptosis, an iron-dependent form of cell death induced by reactive oxygen species (ROS)-mediated lipid peroxidation ( 37 ). Targeting de novo lipogenesis and the Lands cycle has recently been shown to induce ferroptosis in KRAS-mutant lung cancer ( 38 ) and we anticipate similar results in mCRPC. These new findings have opened new possibilities for combinatorial treatments.…”

Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy

“…β-oxidation and de novo lipogenesis, and that this can be exploited for therapeutic gain (Padanad et al, 2016;Gouw et al, 2017;Bartolacci et al, 2021). The role of mutant KRAS in FA oxidation has been reported in a transgenic mouse model that expresses the doxycycline (doxy)-inducible KRAS transgene (KRAS G12D ) in the respiratory epithelium (Padanad et al, 2016).…”

“…Therefore, it may represent a good therapeutic target. Even though a specific inhibitor of ACSL3 is not available, yet, evidence indicates that inhibition of FASN has effects similar to ACSL3 silencing, opening to new possible therapeutic strategies in NSCLC (Bartolacci et al, 2017(Bartolacci et al, , 2021. The role of KRAS in inducing lipogenesis is highlighted by the upregulation of FASN along with other enzymes that control FA metabolism, such as ATP citrate lyase (ACLY) and acetyl-coenzyme A carboxylase (ACC) in the KRAS G12D LC model.…”

“…LPCAT3 preferentially mediates the insertion of AA into membrane PL by re-acylating LysoPL, mostly lysophosphatidylcholines (LysoPC) and lysophosphatidylethanolamines (LysoPE) (Eto et al, 2012;Wang and Tontonoz, 2019;Bartolacci et al, 2021). However, LPCAT3 can insert both PUFA-and MUFA-CoA esters (Hu et al, 2017;Bartolacci et al, 2021).…”

“…LPCAT3 preferentially mediates the insertion of AA into membrane PL by re-acylating LysoPL, mostly lysophosphatidylcholines (LysoPC) and lysophosphatidylethanolamines (LysoPE) (Eto et al, 2012;Wang and Tontonoz, 2019;Bartolacci et al, 2021). However, LPCAT3 can insert both PUFA-and MUFA-CoA esters (Hu et al, 2017;Bartolacci et al, 2021). Thus, our current understanding is that the requirement for LPCAT3 in ferroptosis might depend on the pool of available FA, the cell-type and the ferroptotic stimulus.…”