Reverse transcriptase inhibition disrupts repeat element life cycle in colorectal cancer Journal Article
| Authors: | Rajurkar, M.; Parikh, A. R.; Solovyov, A.; You, E.; Kulkarni, A. S.; Chu, C.; Xu, K. H.; Jaicks, C.; Taylor, M. S.; Wu, C.; Alexander, K. A.; Good, C. R.; Szabolcs, A.; Gerstberger, S.; Tran, A. V.; Xu, N.; Ebright, R. Y.; Van Seventer, E. E.; Vo, K. D.; Tai, E. C.; Lu, C.; Joseph-Chazan, J.; Raabe, M. J.; Nieman, L. T.; Desai, N.; Arora, K. S.; Ligorio, M.; Thapar, V.; Cohen, L.; Garden, P. M.; Senussi, Y.; Zheng, H.; Allen, J. N.; Blaszkowsky, L. S.; Clark, J. W.; Goyal, L.; Wo, J. Y.; Ryan, D. P.; Corcoran, R. B.; Deshpande, V.; Rivera, M. N.; Aryee, M. J.; Hong, T. S.; Berger, S. L.; Walt, D. R.; Burns, K. H.; Park, P. J.; Greenbaum, B. D.; Ting, D. T. |
| Article Title: | Reverse transcriptase inhibition disrupts repeat element life cycle in colorectal cancer |
| Abstract: | Altered RNA expression of repetitive sequences and retrotransposition are fre-quently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstra-tion of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements. SIGNIFICANCE: Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anti-cancer therapeutic strategy. © 2022 American Association for Cancer Research. |
| Keywords: | genetics; interferon; animal; metabolism; animals; protein p53; colorectal neoplasms; rna; dna; colorectal tumor; tumor suppressor protein p53; antivirus agent; life cycle stages; lamivudine; antiviral agents; interferons; rna directed dna polymerase; humans; human; rna-directed dna polymerase; life cycle stage |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-06-01 |
| Start Page: | 1462 |
| End Page: | 1481 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-1117 |
| PUBMED: | 35320348 |
| PROVIDER: | scopus |
| PMCID: | PMC9167735 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2022 -- Source: Scopus |
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