Targeted Activation of Ferroptosis in Colorectal Cancer via LGR4 Targeting Overcomes Acquired Drug Resistance

Overcoming Acquired Resistance in Colorectal Cancer by Targeting LGR4

Research Background: Acquired drug resistance is a major obstacle in cancer treatment and a leading cause of cancer-related deaths. However, the mechanisms of resistance are diverse, and how to specifically target resistant cancer cells remains a significant clinical challenge. Activation of the Wnt pathway can maintain cancer stem cells and induce chemotherapy resistance. Therefore, targeting the Wnt pathway is considered a promising strategy to overcome tumor resistance.

Researchers and Publication: This research was conducted by Professor Chen Quan’s research group at Nankai University. The paper was published in the April 2024 issue of Nature-Cancer. The corresponding authors of the paper are Professor Chen Quan from Nankai University, Researcher Du Lei from the Institute of Animal Research, Chinese Academy of Sciences, and Professor Hu Gang from Nankai University.

Research Process: 1) The researchers established a library of 22 tumor stem cell lines derived from colorectal cancer patients and induced some of the tumor stem cell lines to acquire resistant phenotypes by repeatedly exposing them to low doses of chemotherapeutic drugs.

2) Transcriptomic analysis revealed that the key Wnt pathway protein LGR4 was significantly upregulated in the acquired drug-resistant tumor stem cell lines. Further experiments confirmed that LGR4-positive tumor cells were more resistant to chemotherapy.

3) The researchers developed a monoclonal antibody (LGR4-mAb) that specifically targets LGR4 through activity screening.

4) LGR4-mAb inhibited LGR4-Wnt pathway activity and enhanced the induction of ferroptosis by chemotherapeutic drugs in tumor stem cell lines and in vivo tumor models.

5) Mechanistic studies revealed that the LGR4-Wnt pathway transcriptionally activated the expression of the ferroptosis inhibitor SLC7A11, thereby inhibiting ferroptosis. LGR4-mAb downregulated SLC7A11 expression, resensitizing tumor cells to ferroptosis induced by chemotherapeutic drugs.

6) In tumor stem cell lines and mouse tumor models, combination treatment with LGR4-mAb significantly enhanced the antitumor efficacy of chemotherapeutic drugs, effectively overcoming acquired resistance.

Research Significance: 1) Elucidated the important role of the LGR4-Wnt pathway in acquired tumor resistance and its molecular mechanism of regulating ferroptosis.

2) Developed the first monoclonal antibody targeting LGR4, providing a new therapeutic approach to overcome tumor resistance.

3) Preclinical data support future clinical trials of combining LGR4-mAb with conventional chemotherapy for the treatment of relapsed or resistant patients.

4) This research laid the foundation for designing more novel anti-cancer drugs targeting the Wnt/ferroptosis pathway.

This original research work not only provides insights into the molecular mechanisms of acquired drug resistance in tumor cells but also develops a promising targeted therapy strategy with potential for clinical translation, bringing new hope for overcoming tumor recurrence and resistance.