Open AccessLDH‐A negatively regulates dMMR in colorectal cancer
Author(s) -
Zhang Yongjie,
Li Juan,
Wang Bo,
Chen Ting,
Chen Yun,
Ma Wen
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15020
Subject(s) - colorectal cancer , lactate dehydrogenase , cancer research , in vivo , cancer , lactate dehydrogenase a , blockade , biomarker , medicine , enzyme , chemistry , biology , biochemistry , genetics , receptor
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.