Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

Mihir Rajurkar, Aparna R. Parikh, Alexander Solovyov, Eunae You, Anupriya S. Kulkarni, Chong Chu, Katherine H. Xu, Christopher Jaicks, Martin S. Taylor, Connie Wu, Katherine A. Alexander, Charly R. Good, Annamaria Szabolcs, Stefanie Gerstberger, Antuan V. Tran, Nova Xu, Richard Y. Ebright, Emily E. Van Seventer, Kevin D. Vo, Eric C. TaiChenyue Lu, Jasmin Joseph-Chazan, Michael J. Raabe, Linda T. Nieman, Niyati Desai, Kshitij S. Arora, Matteo Ligorio, Vishal Thapar, Limor Cohen, Padric M. Garden, Yasmeen Senussi, Hui Zheng, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Lipika Goyal, Jennifer Y. Wo, David P. Ryan, Ryan B. Corcoran, Vikram Deshpande, Miguel N. Rivera, Martin J. Aryee, Theodore S. Hong, Shelley L. Berger, David R. Walt, Kathleen H. Burns, Peter J. Park, Benjamin D. Greenbaum, David T. Ting

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1462-1481
Number of pages20
JournalCancer discovery
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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