The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma
Open accessAbstract
Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
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“Recently, an atropisomeric inhibitor directly targeting mutant KRAS(G12C), a specific mutation in 11%-16% of LUAD, has been reported to achieve benefits in mice and in clinical trials (6-9).”
BackgroundOncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
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Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043
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Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., et al. (2013) · Nature · doi:10.1038/nature12040 · Cited by 1,990
Cited by
Targeting Ferroptosis as a Vulnerability in Cancer
Lei, G., Zhuang, L., & Gan, B. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00459-0 · Cited by 2,252
BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer
Li, K., Liu, Y., Ding, Y., Zhang, Z., Feng, J., Hu, J., Chen, J., Lian, Z., Chen, Y., Hu, K., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci161308 · Cited by 37
Self-citationShining a light on metabolic vulnerabilities in non-small cell lung cancer
Dowling, C. M., Zhang, H., Chonghaile, T. N., & Wong, K.-K. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188462 · Cited by 26
Metadata
- Authors
- Hu, K., Li, K., Lv, J., Feng, J., Chen, J., Wu, H., Cheng, F., Jiang, W., Wang, J., Pei, H., Chiao, P. J., Cai, Z., Chen, Y., Liu, M., & Pang, X.
- Venue
- Journal of Clinical Investigation
- Published
- 2020-03-03
- Volume
- 130
- Issue
- 4
- Pages
- 1752-1766
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- OpenAlex
- W2998103954
- Cited by
- 404
- References
- 58
- FWCI
- 13.08
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Hu, K., Li, K., Lv, J., Feng, J., Chen, J., Wu, H., Cheng, F., Jiang, W., Wang, J., Pei, H., Chiao, P. J., Cai, Z., Chen, Y., Liu, M., & Pang, X. (2020). Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. Journal of Clinical Investigation. https://doi.org/10.1172/jci124049
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