期刊
SCIENCE ADVANCES
卷 6, 期 6, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav7416
关键词
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资金
- Basic Science Research Program through the National Research Foundation of Korea [NRF-2016R1C1B2009886]
- KAIST Future Systems Healthcare Project - Korean government Ministry of Science and ICT (MSIT) [KAISTHEALTHCARE42]
- KAIST long-term Undergraduate Research Participation (URP) program [18-C-01]
- NRF grant - MSIT [NRF-2019R1C1C1010482]
Secondary drug resistance stems from dynamic clonal evolution during the development of a prior primary resistance. This collateral type of resistance is often a characteristic of cancer recurrence. Yet, mechanisms that drive this collateral resistance and their drug-specific trajectories are still poorly understood. Using resistance selection and small-scale pharmacological screens, we find that cancer cells with primary acquired resistance to the microtubule-stabilizing drug paclitaxel often develop tolerance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), leading to formation of more stable resistant cell populations. We show that paclitaxel-resistant cancer cells follow distinct selection paths under EGFR-TKIs by enriching the stemness program, developing a highly glycolytic adaptive stress response, and rewiring an apoptosis control pathway. Collectively, our work demonstrates the alterations in cellular state stemming from paclitaxel failure that result in collateral resistance to EGFR-TKIs and points to new exploitable vulnerabilities during resistance evolution in the second-line treatment setting.
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