NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements.Ĭolorectal 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. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. 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.
Cancer element trial#
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. 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. 13 Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, New York.Īltered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression.12 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.11 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.10 Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.9 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.8 Epigenetics Institute, Departments of Cell and Developmental Biology, Genetics, and Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.7 Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, Massachusetts.
6 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.5 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.4 Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.3 Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.2 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.1 Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
0 kommentar(er)
