Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Cancer Discov. 2022 Jun 2;12(6):1462-1481. doi: 10.1158/2159-8290.CD-21-1117.
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.
重复序列和逆转录转座的 RNA 表达改变在结直肠癌中经常出现，这表明重复活动在癌症进展中具有功能重要性。我们展示了核苷逆转录酶抑制剂 3TC 在结直肠癌细胞的临床前模型中靶向这些重复元件的活性，其对与 p53 突变细胞系相关的 p53 直接结合到重复元件的直接结合具有优先作用。我们将这些发现转化为转移性结直肠癌的单药 3TC 治疗的人类 II 期临床试验，证明了 32 名患者中有 9 名具有临床获益。对 3TC 对结直肠肿瘤球体的影响进行分析表明，免疫原性 RNA：DNA 杂交物的积累与干扰素反应基因和 DNA 损伤反应的诱导有关。表观遗传和 DNA 损伤剂诱导重复 RNA，并与 3TC 具有增强的细胞毒性。这些发现通过靶向重复元件的病毒模拟物，确定了结直肠癌的脆弱性。
结直肠癌表达丰富的重复元件，这些元件具有类似于病毒的生命周期，可以用常用于病毒疾病的核苷逆转录酶抑制剂 (NRTI) 进行治疗。NRTIs 诱导 DNA 损伤和干扰素反应，为新的抗癌治疗策略提供了依据。本文在本期的特色文章中进行了强调，第 1397 页。
