Rajurkar, Mihir, Parikh, Aparna R, Solovyov, Alexander, You, Eunae, Kulkarni, Anupriya S, Chu, Chong, Xu, Katherine H, Jaicks, Christopher, Taylor, Martin S, Wu, Connie, Alexander, Katherine A, Good, Charly R, Szabolcs, Annamaria, Gerstberger, Stefanie, Tran, Antuan V, Xu, Nova, Ebright, Richard Y, Van Seventer, Emily E, Vo, Kevin D, Tai, Eric C, Lu, Chenyue, Joseph-Chazan, Jasmin, Raabe, Michael J, Nieman, Linda T, Desai, Niyati, Arora, Kshitij S, Ligorio, Matteo, Thapar, Vishal, Cohen, Limor, Garden, Padric M, Senussi, Yasmeen, Zheng, Hui, Allen, Jill N, Blaszkowsky, Lawrence S, Clark, Jeffrey W, Goyal, Lipika, Wo, Jennifer Y, Ryan, David P, Corcoran, Ryan B, Deshpande, Vikram, Rivera, Miguel N, Aryee, Martin J, Hong, Theodore S, Berger, Shelley L, Walt, David R, Burns, Kathleen H, Park, Peter J, Greenbaum, Benjamin D, Ting, David T (June 2022) Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discovery, 12 (6). pp. 1462-1481. ISSN 2159-8274
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Abstract
Altered RNA expression of repetitive sequences and retrotransposition are frequently 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 demonstration 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. 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 anticancer therapeutic strategy.
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