期刊
CANCERS
卷 12, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/cancers12030685
关键词
colorectal cancer; cetuximab; drug resistance; Vitamin C; glucose metabolism; oxidative stress; ROS; ferroptosis
类别
资金
- AIRC [20236]
- Fondazione AIRC [21091]
- European Community's Seventh Framework Programme [602901]
- H2020 grant [635342-2]
- IMI [115749]
- AIRC IG [16788, 17707, 20685, 21923, 18532, 20697]
- TRANSCAN-2 JTC 2014 contract [TRS-2015-00000060]
- TRANSCAN-2 JTC 2014 TACTIC
- European Research Council Consolidator Grant [724748]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute
- Ministero Salute, RC 2019
- AIRC-CRUK-FC AECC Accelerator Award [22795]
- European Research Council (ERC) [724748] Funding Source: European Research Council (ERC)
The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRC RAS/BRAF wild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies.
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