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. Tai; Chenyue 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

doi:10.1158/2159-8290.CD-21-1117

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 journal › Article › peer-review

14 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 language	English (US)
Pages (from-to)	1462-1481
Number of pages	20
Journal	Cancer discovery
Volume	12
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-21-1117
State	Published - Jun 1 2022
Externally published	Yes

ASJC Scopus subject areas

Oncology

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10.1158/2159-8290.CD-21-1117

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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., ... Ting, D. T. (2022). Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer discovery, 12(6), 1462-1481. https://doi.org/10.1158/2159-8290.CD-21-1117

Rajurkar, M, Parikh, AR, Solovyov, A, You, E, Kulkarni, AS, Chu, C, Xu, KH, Jaicks, C, Taylor, MS, Wu, C, Alexander, KA, Good, CR, Szabolcs, A, Gerstberger, S, Tran, AV, Xu, N, Ebright, RY, Van Seventer, EE, Vo, KD, Tai, EC, Lu, C, Joseph-Chazan, J, Raabe, MJ, Nieman, LT, Desai, N, Arora, KS, Ligorio, M, Thapar, V, Cohen, L, Garden, PM, Senussi, Y, Zheng, H, Allen, JN, Blaszkowsky, LS, Clark, JW, Goyal, L, Wo, JY, Ryan, DP, Corcoran, RB, Deshpande, V, Rivera, MN, Aryee, MJ, Hong, TS, Berger, SL, Walt, DR, Burns, KH, Park, PJ, Greenbaum, BD & Ting, DT 2022, 'Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer', Cancer discovery, vol. 12, no. 6, pp. 1462-1481. https://doi.org/10.1158/2159-8290.CD-21-1117

@article{d616af5a16db4daa8794686e2b5fbf90,

title = "Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer",

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.",

author = "Mihir Rajurkar and Parikh, {Aparna R.} and Alexander Solovyov and Eunae You and Kulkarni, {Anupriya S.} and Chong Chu and Xu, {Katherine H.} and Christopher Jaicks and Taylor, {Martin S.} and Connie Wu and Alexander, {Katherine A.} and Good, {Charly R.} and Annamaria Szabolcs and Stefanie Gerstberger and Tran, {Antuan V.} and Nova Xu and Ebright, {Richard Y.} and {Van Seventer}, {Emily E.} and Vo, {Kevin D.} and Tai, {Eric C.} and Chenyue Lu and Jasmin Joseph-Chazan and Raabe, {Michael J.} and Nieman, {Linda T.} and Niyati Desai and Arora, {Kshitij S.} and Matteo Ligorio and Vishal Thapar and Limor Cohen and Garden, {Padric M.} and Yasmeen Senussi and Hui Zheng and Allen, {Jill N.} and Blaszkowsky, {Lawrence S.} and Clark, {Jeffrey W.} and Lipika Goyal and Wo, {Jennifer Y.} and Ryan, {David P.} and Corcoran, {Ryan B.} and Vikram Deshpande 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.}",

note = "Funding Information: We are grateful to Laura Libby for mouse colony care, Emily Silva, and Danielle Bestoso for administrative support. We appreciate productive discussions with Arnold Levine and Junne Kamihara on this work. This study was supported by NIH grants R01CA240924 (D.T. Ting and B.D. Greenbaum), U01CA228963 (B.D. Greenbaum and D.T. Ting), R01GM130680 (K.H. Burns), R01CA240816 (K.H. Burns), T32GM007753 (R.Y. Ebright), 1F30CA232407-01 (R.Y. Ebright); Gateway for Cancer Research G-17-1000 (D.T. Ting and A.R. Parikh); National Science Foundation NSF PHY-1549535 (D.T. Ting and B.D. Greenbaum); Burroughs Wellcome Fund 1010968.01 (D.T. Ting); V Foundation for Cancer Research D2015-034 (M. Rajurkar); SU2C AACR-PS-17 (D.T. Ting and S.L. Berger); SU2C-Lustgarten Foundation 2015-002 (D.T. Ting and B.D. Greenbaum); Affymetrix, Inc. (D.T. Ting, K.S. Arora, N. Desai, M.N. Rivera, and V. Deshpande); ACD-Biotechne (D.T. Ting, A.S. Kulkarni, M.N. Rivera, and V. Deshpande); Robert L. Fine Cancer Research Foundation (D.T. Ting); and The Pershing Square Sohn Prize–Mark Foundation Fellowship (B.D. Greenbaum). Funding Information: A.R. Parikh reports personal fees from C2I Genomics, Guardant, Checkmate, Natera, Eli Lilly, Pfizer, Roche, Inivata, and Bio Fidelity, and other support from Puretech, PMV Pharma, Plexxicon, Takeda, Bristol Myers Squibb, Novartis, Mirati, Genentech, and Daiichi Sankyo outside the submitted work. A. Solovyov reports grants from the NIH during the conduct of the study; personal fees from ROME Therapeutics outside the submitted work; and a patent for targeting repeat RNAs and their use as novel biomarkers pending. M.S. Taylor reports personal fees from ROME Therapeutics outside the submitted work. C. Wu reports a patent for ultrasensitive assays for detection of ORF1p in biofluids pending. R.Y. Ebright reports personal fees from Nextech Invest outside the submitted work. E.E. Van Seventer reports personal fees and other support from Blueprint Medicines outside the submitted work. N. Desai reports other support from ACD during the conduct of the study, as well as other support from ACD outside the submitted work. M. Ligorio reports a patent for treatments pending unrelated to the topic of this article. L. Goyal serves as a consultant or advisory board member for Alentis Therapeutics AG, AstraZeneca, Black Diamond, Basilea, Exelixis, H3 Biomedicine, Incyte Corporation, QED Therapeutics, Servier, Sirtex Medical Ltd., and Taiho Oncology; reports grant/research support (to institution) from Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics, Taiho Oncology, Leap Therapeutics, Bristol Meyers Squibb, Nucana, and Servier; and is on the Data Safety Monitoring Committee for AstraZeneca. D.P. Ryan reports personal fees and other support from MPM, personal fees from Boehringer Ingelheim, UpToDate, and McGraw Hill, grants from SU2C, and other support from Exact Sciences during the conduct of the study. R.B. Corcoran reports personal fees from AbbVie, Elicio, FOG Pharma, Guardant Health, Navire, Qiagen, Syndax, Taiho, and Zikani Therapeutics, other support from Avidity Biosciences, grants and personal fees from Asana Biosciences and Pfizer, personal fees and other support from C4 Therapeutics, Cogent Biosciences, Kinnate Biopharma, Nested Ther-apteutics, Interline Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines, and Theonys, and grants from Novartis and Lilly outside the submitted work. M.N. Rivera reports nonfinancial support from ACD during the conduct of the study, as well as nonfinancial support from Merck Serono outside the submitted work. M.J. Aryee reports personal fees from SeQure Dx outside the submitted work. T.S. Hong reports personal fees from Merck, Novocure, Boston Scientific, Inviata, Merck, GlaxoSmithKline, PanTher Therapeutics, and the Lustgarten Foundation, and grants from Taiho, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, IntraOp, and Ipsen outside the submitted work. D.R. Walt reports personal fees from Quanterix Corporation outside the submitted work; multiple patents issued, licensed, and with royalties paid from Quanterix Corporation; and is a founder, equity holder, and director of Quanterix Corporation. D.R. Walt{\textquoteright}s interests were reviewed and are managed by Brigham and Women{\textquoteright}s Hospital and Mass General Brigham in accordance with their conflict of interest policies. K.H. Burns reports personal fees and other support from ROME Therapeutics, Transposon Therapeutics, and Oncolinea Pharmaceuticals outside the submitted work, as well as a patent for LINE-1–encoded ORF2p for cancer therapeutics licensed to Axcelius Holding Company, LLC and a patent for detection of ORF1p in biofluids pending. B.D. Green-baum reports grants from Merck and Bristol Myers Squibb, and personal fees from ROME Therapeutics outside the submitted work, as well as a patent for WO-2019157087-A1 issued. D.T. Ting reports grants from ACD/Biotechne, the NIH/NCI, the National Science Foundation, the Robert L. Fine Cancer Research Foundation, the SU2C–Lustgarten Foundation 2015-002, Affymetrix, SU2C AACR-PS17, and the Burroughs Wellcome Fund during the conduct of the study; personal fees and other support from ROME Therapeutics, personal fees from Tekla Capital, Ikena Oncology, NanoString Technologies, Pfizer, and Foundation Medicine Inc., and other support from PanTher Therapeutics and TellBio, Inc. outside the submitted work; and a patent for biomarkers of cancer issued and licensed to ROME Therapeutics, a patent for targeting human satellite II (HSATII) issued and licensed to ROME Therapeutics, and a patent for repeat RNA as biomarkers of tumor immune response pending and licensed to ROME Therapeutics. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = jun,

day = "1",

doi = "10.1158/2159-8290.CD-21-1117",

language = "English (US)",

volume = "12",

pages = "1462--1481",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "6",

}

TY - JOUR

T1 - Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

AU - Rajurkar, Mihir

AU - Parikh, Aparna R.

AU - Solovyov, Alexander

AU - You, Eunae

AU - Kulkarni, Anupriya S.

AU - Chu, Chong

AU - Xu, Katherine H.

AU - Jaicks, Christopher

AU - Taylor, Martin S.

AU - Wu, Connie

AU - Alexander, Katherine A.

AU - Good, Charly R.

AU - Szabolcs, Annamaria

AU - Gerstberger, Stefanie

AU - Tran, Antuan V.

AU - Xu, Nova

AU - Ebright, Richard Y.

AU - Van Seventer, Emily E.

AU - Vo, Kevin D.

AU - Tai, Eric C.

AU - Lu, Chenyue

AU - Joseph-Chazan, Jasmin

AU - Raabe, Michael J.

AU - Nieman, Linda T.

AU - Desai, Niyati

AU - Arora, Kshitij S.

AU - Ligorio, Matteo

AU - Thapar, Vishal

AU - Cohen, Limor

AU - Garden, Padric M.

AU - Senussi, Yasmeen

AU - Zheng, Hui

AU - Allen, Jill N.

AU - Blaszkowsky, Lawrence S.

AU - Clark, Jeffrey W.

AU - Goyal, Lipika

AU - Wo, Jennifer Y.

AU - Ryan, David P.

AU - Corcoran, Ryan B.

AU - Deshpande, Vikram

AU - Rivera, Miguel N.

AU - Aryee, Martin J.

AU - Hong, Theodore S.

AU - Berger, Shelley L.

AU - Walt, David R.

AU - Burns, Kathleen H.

AU - Park, Peter J.

AU - Greenbaum, Benjamin D.

AU - Ting, David T.

N1 - Funding Information: We are grateful to Laura Libby for mouse colony care, Emily Silva, and Danielle Bestoso for administrative support. We appreciate productive discussions with Arnold Levine and Junne Kamihara on this work. This study was supported by NIH grants R01CA240924 (D.T. Ting and B.D. Greenbaum), U01CA228963 (B.D. Greenbaum and D.T. Ting), R01GM130680 (K.H. Burns), R01CA240816 (K.H. Burns), T32GM007753 (R.Y. Ebright), 1F30CA232407-01 (R.Y. Ebright); Gateway for Cancer Research G-17-1000 (D.T. Ting and A.R. Parikh); National Science Foundation NSF PHY-1549535 (D.T. Ting and B.D. Greenbaum); Burroughs Wellcome Fund 1010968.01 (D.T. Ting); V Foundation for Cancer Research D2015-034 (M. Rajurkar); SU2C AACR-PS-17 (D.T. Ting and S.L. Berger); SU2C-Lustgarten Foundation 2015-002 (D.T. Ting and B.D. Greenbaum); Affymetrix, Inc. (D.T. Ting, K.S. Arora, N. Desai, M.N. Rivera, and V. Deshpande); ACD-Biotechne (D.T. Ting, A.S. Kulkarni, M.N. Rivera, and V. Deshpande); Robert L. Fine Cancer Research Foundation (D.T. Ting); and The Pershing Square Sohn Prize–Mark Foundation Fellowship (B.D. Greenbaum). Funding Information: A.R. Parikh reports personal fees from C2I Genomics, Guardant, Checkmate, Natera, Eli Lilly, Pfizer, Roche, Inivata, and Bio Fidelity, and other support from Puretech, PMV Pharma, Plexxicon, Takeda, Bristol Myers Squibb, Novartis, Mirati, Genentech, and Daiichi Sankyo outside the submitted work. A. Solovyov reports grants from the NIH during the conduct of the study; personal fees from ROME Therapeutics outside the submitted work; and a patent for targeting repeat RNAs and their use as novel biomarkers pending. M.S. Taylor reports personal fees from ROME Therapeutics outside the submitted work. C. Wu reports a patent for ultrasensitive assays for detection of ORF1p in biofluids pending. R.Y. Ebright reports personal fees from Nextech Invest outside the submitted work. E.E. Van Seventer reports personal fees and other support from Blueprint Medicines outside the submitted work. N. Desai reports other support from ACD during the conduct of the study, as well as other support from ACD outside the submitted work. M. Ligorio reports a patent for treatments pending unrelated to the topic of this article. L. Goyal serves as a consultant or advisory board member for Alentis Therapeutics AG, AstraZeneca, Black Diamond, Basilea, Exelixis, H3 Biomedicine, Incyte Corporation, QED Therapeutics, Servier, Sirtex Medical Ltd., and Taiho Oncology; reports grant/research support (to institution) from Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics, Taiho Oncology, Leap Therapeutics, Bristol Meyers Squibb, Nucana, and Servier; and is on the Data Safety Monitoring Committee for AstraZeneca. D.P. Ryan reports personal fees and other support from MPM, personal fees from Boehringer Ingelheim, UpToDate, and McGraw Hill, grants from SU2C, and other support from Exact Sciences during the conduct of the study. R.B. Corcoran reports personal fees from AbbVie, Elicio, FOG Pharma, Guardant Health, Navire, Qiagen, Syndax, Taiho, and Zikani Therapeutics, other support from Avidity Biosciences, grants and personal fees from Asana Biosciences and Pfizer, personal fees and other support from C4 Therapeutics, Cogent Biosciences, Kinnate Biopharma, Nested Ther-apteutics, Interline Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines, and Theonys, and grants from Novartis and Lilly outside the submitted work. M.N. Rivera reports nonfinancial support from ACD during the conduct of the study, as well as nonfinancial support from Merck Serono outside the submitted work. M.J. Aryee reports personal fees from SeQure Dx outside the submitted work. T.S. Hong reports personal fees from Merck, Novocure, Boston Scientific, Inviata, Merck, GlaxoSmithKline, PanTher Therapeutics, and the Lustgarten Foundation, and grants from Taiho, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, IntraOp, and Ipsen outside the submitted work. D.R. Walt reports personal fees from Quanterix Corporation outside the submitted work; multiple patents issued, licensed, and with royalties paid from Quanterix Corporation; and is a founder, equity holder, and director of Quanterix Corporation. D.R. Walt’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. K.H. Burns reports personal fees and other support from ROME Therapeutics, Transposon Therapeutics, and Oncolinea Pharmaceuticals outside the submitted work, as well as a patent for LINE-1–encoded ORF2p for cancer therapeutics licensed to Axcelius Holding Company, LLC and a patent for detection of ORF1p in biofluids pending. B.D. Green-baum reports grants from Merck and Bristol Myers Squibb, and personal fees from ROME Therapeutics outside the submitted work, as well as a patent for WO-2019157087-A1 issued. D.T. Ting reports grants from ACD/Biotechne, the NIH/NCI, the National Science Foundation, the Robert L. Fine Cancer Research Foundation, the SU2C–Lustgarten Foundation 2015-002, Affymetrix, SU2C AACR-PS17, and the Burroughs Wellcome Fund during the conduct of the study; personal fees and other support from ROME Therapeutics, personal fees from Tekla Capital, Ikena Oncology, NanoString Technologies, Pfizer, and Foundation Medicine Inc., and other support from PanTher Therapeutics and TellBio, Inc. outside the submitted work; and a patent for biomarkers of cancer issued and licensed to ROME Therapeutics, a patent for targeting human satellite II (HSATII) issued and licensed to ROME Therapeutics, and a patent for repeat RNA as biomarkers of tumor immune response pending and licensed to ROME Therapeutics. No disclosures were reported by the other authors. Publisher Copyright: © 2022 American Association for Cancer Research.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85131268662&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-21-1117

DO - 10.1158/2159-8290.CD-21-1117

M3 - Article

C2 - 35320348

AN - SCOPUS:85131268662

SN - 2159-8274

VL - 12

SP - 1462

EP - 1481

JO - Cancer discovery

JF - Cancer discovery

IS - 6

ER -

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

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