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LDH-A negatively regulates dMMR in colorectal cancer
Yongjie Zhang1, Juan Li1, Bo Wang2
1Department of Medical Oncology, Huai'an Hospital Affiliated with Xuzhou Medical University, Huai'an, China.
Abstract:
Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH-A) is the rate-limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here show that LDH-A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH-A inhibition can improve the efficacy of PD-1 blockade in a pMMR CRC xenograft model. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH-A and dMMR status. Moreover, patients with both low LDH-A expression and dMMR exhibited better disease-free survival compared with patients with other combinations. The close correlation of LDH-A and dMMR may offer a promising therapeutic strategy in which the combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.
Insights
Lactate dehydrogenase A (LDH-A) promotes colorectal cancer (CRC) cell proliferation. Inhibiting LDH-A enhances immunotherapy efficacy in mismatch repair proficient (pMMR) CRC, suggesting a new treatment strategy.
Area of Science:
- Oncology
- Cancer Metabolism
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) are effective for mismatch repair deficient (dMMR) tumors but not for mismatch repair proficient (pMMR) colorectal cancer (CRC), which represents 85% of cases.
- Lactate dehydrogenase A (LDH-A) is a key enzyme in glycolysis, converting pyruvate to lactate.
Purpose of the Study:
- To investigate the relationship between LDH-A and dMMR status in CRC.
- To explore LDH-A as a therapeutic target for pMMR CRC patients unresponsive to ICIs.
Main Methods:
- In vitro and in vivo experiments assessing LDH-A's role in CRC cell proliferation and MMR protein regulation.
- Evaluation of LDH-A inhibition combined with PD-1 blockade in a pMMR CRC xenograft model.
- Statistical analysis of LDH-A expression and dMMR status in 186 CRC specimens.
Main Results:
- LDH-A was found to promote proliferation in both dMMR and pMMR CRC cells by positively regulating MMR proteins.
- Inhibition of LDH-A enhanced the efficacy of PD-1 blockade in pMMR CRC xenografts.
- A significant correlation was observed between LDH-A expression and dMMR status in CRC patients.
- Patients with low LDH-A expression and dMMR showed improved disease-free survival.
Conclusions:
- LDH-A plays a crucial role in CRC progression and is closely correlated with dMMR status.
- Combining LDH-A inhibitors with ICIs presents a promising therapeutic strategy to improve clinical outcomes for pMMR CRC patients.
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