# Targeting cysteine import to induce ferroptotic cell death in pancreatic cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $385,147

## Abstract

Abstract:
 Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult challenges in oncology. Activating
mutations in the K-ras oncogene are found in 95% of PDA cases, but agents are not yet available that can
effectively target this (or any other) high prevalence alteration in PDA. An alternative strategy is to target critical
biological processes that PDA cells depend on but normal cells can forego. An example of this is the import of
exogenous cysteine (in the oxidized form of cystine) via the cystine/glutamate antiporter called System xc−.
The inhibition of System xc− in many cancer cell lines has been shown to induce a peculiar form of non-
apoptotic cell death, called ferroptosis, which is mechanistically distinct from necroptosis, autophagy,
parthanatos, and other forms of non-apoptotic cell death. It is characterized by the rapid, iron-dependent
accumulation of lipid ROS leading to loss of membrane integrity in the absence of DNA cleavage. Despite the
dramatic effects of System xc− inhibition in tumor cells, germline System xc− knockout mice are viable and
healthy as adults, proving that normal cells do not usually require cystine import. Cysteine is the rate-limiting
precursor for the synthesis of glutathione (GSH), a non-protein tripeptide that is critical for the detoxification of
reactive oxygen species (ROS). Ferroptosis can also be induced by inhibitors of glutathione peroxidase 4
(GPX4) which detoxifies lipid peroxides using GSH as a co-factor. Yet depletion of GSH itself has not been
shown to induce ferroptosis, for reasons that are unclear. We hypothesize that depletion of cysteine is
qualitatively distinct from the depletion of glutathione and that additional cysteine−derived metabolites play a
critical role in the detoxification of lipid ROS and control of ferroptosis.
 Several inhibitors of System xc− have been identified that effectively induce ferroptosis in vitro, including
erastin, sulfasalazine, and sorafenib, and new inhibitors are rapidly being developed. The overarching goal of
this proposal is to determine the underlying mechanisms of ferroptosis induction through System xc− inhibition,
including the identification of determinants of ferroptosis sensitivity. We bring to bear a range of innovative
tools, including cysteine and methionine carbon labeling, mass spectrometry, chemical biology approaches,
inducible lentiviral shRNA knockdown of key metabolic enzymes, systems biology techniques, small animal
imaging, and translational therapeutics using genetically engineered mouse models. In addition to 2D cell line
and organoid culture models, we also present pilot data from a sophisticated genetically engineered mouse
model that enables the acute deletion of System xc− in established K-ras/p53 mutant pancreatic tumors. This
six-allele dual recombinase mouse strategy provides an ideal genetic strategy for the evaluation of System xc−
function in PDA and serves as a source for genetically−defined primary cells to ...

## Key facts

- **NIH application ID:** 10088424
- **Project number:** 5R01CA215607-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Kenneth P. Olive
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,147
- **Award type:** 5
- **Project period:** 2017-03-08 → 2022-03-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088424

## Citation

> US National Institutes of Health, RePORTER application 10088424, Targeting cysteine import to induce ferroptotic cell death in pancreatic cancer (5R01CA215607-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10088424. Licensed CC0.

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