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Cited by 61Chromosomal and Genetic VariationsCancer-related molecular mechanisms researchTelomeres, Telomerase, and Senescence

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

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Rajurkar, Mihir, Parikh, Aparna R., Solovyov, Alexander, You, Eunae, Kulkarni, Anupriya S., Chu, Chong, Xu, Katherine H., Jaicks, Christopher +41 more·2022·Cancer Discovery
DOI 10.1158/2159-8290.cd-21-1117PMC PMC9167735

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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. 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 anticancer therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1397

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  • Noncoding hSATII RNA is highly expressed in most cancer cells and tissues.

    “Previous reports demonstrated that noncoding hSATII RNA is highly expressed in most cancer cells and tissues (27–32).”

    From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [32]

    The Results section (“P53 is a Direct Repressor of Repeat RNA Expression”; page unavailable) reports higher HSATII expression in P53-mutant colorectal cancer cell lines and says satellite repeats are highly expressed in a broad set of cancers. The Results section on DNA damage also reports HSATII RNA in colorectal tumors, particularly after cytotoxic therapy. These passages support cancer-associated expression, but not the claim that HSATII is highly expressed in most cancer cells and tissues. (LLM, conf=0.86)

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Cited by

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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.
Affiliations
  • Harvard University (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Brigham and Women's Hospital (US)
  • University of Pennsylvania (US)
  • 1Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
  • Massachusetts General Hospital (US)
Corresponding author
  • Greenbaum, Benjamin D.
  • Ting, David T.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2022-03-23
Volume
12
Issue
6
Pages
1462-1481
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-21-1117
PMC
PMC9167735
OpenAlex
W4225729206
Cited by
61
References
10
Citations by year
2026: 12 · 2025: 13 · 2024: 14 · 2023: 17 · 2022: 5
FWCI
6.75
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • NIH (R01CA240924, U01CA228963, R01GM130680, R01CA240816, T32GM007753, 1F30CA232407-01)
  • Gateway for Cancer Research (G-17-1000)
  • National Science Foundation (PHY-1549535)
  • Burroughs Wellcome Fund (1010968.01)
  • V Foundation for Cancer Research (D2015-034)
  • SU2C (AACR-PS-17)
  • SU2C-Lustgarten Foundation (2015-002)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
colorectal cancer, nucleoside reverse transcriptase inhibitors, lamivudine, repetitive elements, retrotransposition, TP53 mutation, RNA-DNA hybrids, interferon response, DNA damage response, tumor spheres, metastatic colorectal cancer, monotherapy, epigenetic agents, viral mimicry

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