Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms

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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.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Issue Date
2020-02
Language
English
Article Type
Article
Citation

SCIENCE ADVANCES, v.6, no.6

ISSN
2375-2548
DOI
10.1126/sciadv.aav7416
URI
http://hdl.handle.net/10203/272385
Appears in Collection
MSE-Journal Papers(저널논문)CBE-Journal Papers(저널논문)
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