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Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

Mihir Rajurkar1, Aparna R Parikh1,2, Alexander Solovyov3

  • 1Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts.

Cancer Discovery
|March 23, 2022
PubMed

Insights

Nucleoside reverse transcriptase inhibitors (NRTIs) target repetitive elements in colorectal cancer cells, particularly those with p53 mutations. This approach shows clinical benefit and induces DNA damage and interferon responses, offering a novel cancer therapy.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) exhibits altered RNA expression and retrotransposition of repetitive sequences, suggesting their role in cancer progression.
  • Repetitive elements in CRC possess a viral-like life cycle, presenting a potential therapeutic target.

Purpose of the Study:

  • To investigate the efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) in targeting repetitive elements in colorectal cancer.
  • To explore the mechanisms of NRTI action, including effects on p53-mutant cell lines and the induction of DNA damage and interferon responses.

Main Methods:

  • Preclinical models of colorectal cancer, including cell lines and tumorspheres.
  • Phase II clinical trial of single-agent 3TC (an NRTI) in metastatic colorectal cancer patients.
  • Analysis of RNA:DNA hybrids, interferon response genes, and DNA damage response pathways.

Main Results:

  • The NRTI 3TC demonstrated preferential activity against repeat element activity in colorectal cancer models, especially in p53-mutant cells.
  • Clinical benefit was observed in 9 out of 32 patients with metastatic colorectal cancer treated with 3TC.
  • 3TC treatment led to the accumulation of immunogenic RNA:DNA hybrids, inducing interferon and DNA damage responses in colorectal cancer tumorspheres.

Conclusions:

  • Targeting the viral mimicry of repetitive elements with NRTIs represents a novel therapeutic strategy for colorectal cancer.
  • Combination therapy with epigenetic or DNA-damaging agents may enhance the efficacy of NRTIs in colorectal cancer treatment.

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