Metabolische Vulnerabilität ALK-Inhibitor resistenter EML4-ALK positiver nicht-kleinzelliger Lungenkrebszellen
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Philipps-Universität Marburg
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Abstract
Cancer is responsible for around one fifth of all deaths in Germany. In comparison to other subtypes, lung cancer is the most lethal type. Although the therapeutic options are getting more effective, at some point the occurrence of drug resistance is inevitable. One of the resistance mechanisms is the upregulation of mTOR. Unfortunately, the direct inhibiton of mTOR is currently not as effective as previously thought. Therefore, the focus of todays research is still based on the identification of potential treatment options for tumors with a mTOR-dependent resistance.
As it was shown in preclinical studies, mTOR acts as a dual player in Cisplatin-resistant non-small cell lung cancer (NSCLC) and PI3K-inhibitor resistant breast cancer cells. On one hand mTOR maintains the therapy resistance and on the other it mediates metabolic vulnerability through the suppression of autophagy.
Previous studies could proof that an altered mTOR activity also occurs in some ALK- inhibitor resistant EML4-ALK positive NSCLC. Therefore, the further analysis of the dual role of mTOR in therapy resistant EML4-ALK positive cell clones was an essential part of this project. In order to obtain resistant cell clones we used dose escalation and treated the EML4-ALK positive NSCLC cell line H3122 with the three ALK-inhibitors Crizotinib, Ceritinib and Brigatinib.
Some of the resistant cell clones indeed showed an icreased vulnerability to the treatment with the metabolic drugs 2-DG, DCA and Metformin compared to therapy-naive H3122-cells. In addition, some of these clones also had a basally upregulated mTOR activity. Further analysis of a representatively chosen Brigatinib-resistant cell clone with an augmented metabolic vulnerability and a parallely altered mTOR activity showed that the inhibition of mTORC1 with Everolismus and Rapamycin was neither able to reverse the resistance nor the metabolic vulnerability. Therefore, the development of the therapy-resistant and the metabolically vulnerable phenotype in ALK- inhibitor resistant cell clones seems to be more complex. In addition, it cannot be excluded, that the mechanisms behind the resistance and the metabolic vulnerability are independent from each other.
Based on other observations in this project it is possible that not only mTOR but also the deficiency of mTOR-independent mediators of autophagy or altered levels of the transcription factor cMyc are the key mechanisms mediating the resistance and/or the metabolic vulnerability in some cell clones.
In conclusion it could be proved that the therapy with metablic inhibitiors is indeed effective against ALK-inhibitor resistant EML4-ALK positive lung cancer cells. In order to identify the exact origin of the therapy resistance and the metabolic vulnerable phenotype more analysis is indispensable. Altogether the findings propose that the use of metabolic inhibitors should be considered as a potential therapy option for relapsed EML4-ALK positive NSCLC.
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Created: 2023Issued: 2025-02-12Updated: 2025-02-12
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Medizin
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Philipps-Universität Marburg
Language
ger
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DoctoralThesis
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610
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Eimagh Naeini, Saman: Metabolische Vulnerabilität ALK-Inhibitor resistenter EML4-ALK positiver nicht-kleinzelliger Lungenkrebszellen. : Philipps-Universität Marburg 2025-02-12. DOI: https://doi.org/10.17192/z2023.0617.
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