Details

Autor(en) / Beteiligte

• 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

Titel

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

Ist Teil von

• Cancer discovery, 2022-06, Vol.12 (6), p.1462-1481

Ort / Verlag

United States

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. This article is highlighted in the In This Issue feature, p. 1397.