Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

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.