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    Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

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    Authors
    Ketola, K.
    Kaljunen, H.
    Taavitsainen, S.
    Kaarijärvi, R.
    Järvelä, E.
    Rodriguez Martin, B.
    Haase, K.
    Woodcock, D. J.
    Tubio, J.
    Wedge, David C
    Nykter, M
    Bova, G. S.
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    Affiliation
    Institute of Biomedicine, University of Eastern Finland
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance Analysis (DSER), a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and post-treatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC-3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected post-castration in LuCaP 77 and LuCaP 105 xenograft models and post-chemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.
    Citation
    Ketola K, Kaljunen H, Taavitsainen S, Kaarijärvi R, Järvelä E, Rodriguez Martin B, et al. Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity. Cancer Res. 2021 Aug 4;canres.0371.2021.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/624558
    DOI
    10.1158/0008-5472.CAN-21-0371.
    PubMed ID
    34348967
    Additional Links
    https://dx.doi.org/10.1158/0008-5472.CAN-21-0371.
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-21-0371.
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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