@article {1638817, title = {Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer}, journal = {Cancer Discov}, year = {2022}, month = {2022 Mar 23}, abstract = {Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer (CRC) 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 CRC pre-clinical 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 2 trial of single agent 3TC treatment in metastatic CRC with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on CRC 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 CRC by targeting the viral mimicry of repeat elements.}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-21-1117}, author = {Rajurkar, Mihir and Parikh, Aparna R and Solovyov, Alexander and You, Eunae and Kulkarni, Anupriya S and Chu, Chong and Xu, Katherine H and Jaicks, Christopher and Taylor, Martin S and Wu, Connie and Alexander, Katherine A and Good, Charly R and Szabolcs, Annamaria and Gerstberger, Stefanie and Tran, Antuan V and Xu, Nova and Ebright, Richard Y and Van Seventer, Emily E and Vo, Kevin D and Tai, Eric C and Lu, Chenyue and Joseph-Chazan, Jasmin and Raabe, Michael J and Nieman, Linda T and Desai, Niyati and Arora, Kshitij S and Ligorio, Matteo and Thapar, Vishal and Cohen, Limor and Garden, Padric M and Senussi, Yasmeen and Zheng, Hui and Allen, Jill N and Blaszkowsky, Lawrence S and Clark, Jeffrey W and Goyal, Lipika and Wo, Jennifer Y and Ryan, David P and Corcoran, Ryan B and Deshpande, Vikram and Rivera, Miguel N and Aryee, Martin J and Hong, Theodore S and Berger, Shelley L and Walt, David R and Burns, Kathleen H and Park, Peter J and Greenbaum, Benjamin D and Ting, David T} }