A new means of overcoming chemotherapy resistance

 

Over the past decade, the medical community has made significant breakthroughs in the fight against cancer. However, cancer drug resistance and recurrence remain the leading causes of treatment failure and cancer-related deaths.

Ferroptosis is a regulated mode of necrotic cell death characterized by Fe-dependent accumulation of lipid peroxides, discovered in 2012 by Brent Stockwell’s laboratory at Columbia University. Inactivation of key components of the phospholipid peroxidase GPX4 or the cystine/glutamate reverse transcriptase SLC7A11 leads to depletion of cellular glutathione (GSH), resulting in lipid peroxidation and subsequent ferroptosis. Several oncogenic signaling pathways (e.g., p53, KRAS, and Hippo pathways) have been found to modulate ferroptosis, and these pathways may alter SLC7A11 and GPX4 expression or lipid metabolism to modulate ferroptosis sensitivity and resistance. These studies raise the possibility of exploiting the vulnerability to ferroptosis to combat cancer.

There is growing evidence that several chemotherapeutic agents, including sorafenib and cisplatin, have been found to promote ferroptosis in cancer cells. Combining ferroptosis inducers (e.g., RSL3) with chemotherapeutic agents can achieve synergistic anticancer effects, which appears to be a promising avenue for tumor eradication. However, one important question remains unanswered—how to selectively target the ferroptosis pathway without affecting normal cell growth?

On January 30, 2024, researchers from Nankai University and the Chinese Academy of Sciences jointly published a research paper in the Nature Cancer journal entitled “Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance”.

The study constructed organoids from colorectal cancer patients and found that chemotherapy-resistant tumor organoids exhibited elevated LGR4 expression and activation of the Wnt signaling pathway. The research team developed a monoclonal antibody targeting LGR4, LGR4-mAb, which can effectively inhibit LGR4-Wnt signaling and significantly enhance ferroptosis in chemotherapy-resistant tumor organoids when combined with chemotherapeutic agents, thus opening up a new way of combating refractory and recurrent cancers.

Acquired drug resistance is a major challenge in cancer treatment and a leading cause of cancer death. However, the mechanisms of drug resistance in cancer are diverse, and therapeutic strategies to target drug-resistant cancer cells remain an unsolved clinical problem.

Tumor organoids are able to faithfully reproduce the response of patients to treatment in the clinic and predict sensitivity to chemotherapy and radiotherapy. In this study, the research team constructed a library of patient-derived organoid biospecimens from colorectal cancer and induced acquired resistance by repeated low-level exposure to chemotherapeutic agents. Chemo-sensitivity analysis and transcriptomic analysis revealed that these resistant cancer-like organs exhibited high LGR4 expression and activation of the Wnt signaling pathway.

On this basis, the research team developed a monoclonal antibody, LGR4-mAb, which was able to effectively inhibit the LGR4-Wnt signaling pathway, and more importantly, treatment with LGR4-mAb significantly increased the susceptibility to drug-induced ferroptosis.

Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulates SLC7A11, a key inhibitor of ferroptosis, thereby conferring acquired resistance. When combined with chemotherapeutic agents, LGR4-mAb targeting of Wnt signaling enhances ferroptosis, opening new opportunities to combat refractory and recurrent cancers.