Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity
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.
Affiliation
Institute of Biomedicine, University of Eastern FinlandIssue Date
2021
Metadata
Show full item recordAbstract
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 ResearchDOI
10.1158/0008-5472.CAN-21-0371.PubMed ID
34348967Additional Links
https://dx.doi.org/10.1158/0008-5472.CAN-21-0371.Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-21-0371.
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