Novel LOX inhibitor shows promise in treating cancer
Researchers from the University of Manchester and The Institute of Cancer Research have identified a new pathway involved in the progression of breast cancer, and they have also designed a compound that inhibits this pathway. The study appears in the scientific journal Nature Communications.
A protein called lysyl oxidase (LOX) is an extracellular copper-dependent enzyme that functions in the crosslinking of collagens and elastin. Upregulation of LOX appears to promote the growth and metastasis of the existing tumor and is associated with poor outcome in colon, breast, pancreas, prostate and lung cancers.
In this study, the researchers aimed to determine the mechanism by which LOX contributes to tumor progression. Using breast cancer cell lines, they demonstrated that LOX depletion by shRNA resulted in a reduction in the surface levels of epidermal growth factor receptor (EGFR). Like LOX, EGFR is also linked to tumor growth and spread.
In vivo experiments in mice suggested that removal of the LOX gene from cancer cells could significantly reduce the tumor volume as well as metastases. These mice lived much longer than the control mice. Overall, the findings indicate that LOX might be a therapeutic target for cancer.
To test this hypothesis, the researchers designed a complementary compound called CCT365623, which is much more potent than a common LOX inhibitor known as BAPN. Importantly, this compound can be taken orally, and it is well tolerated. The researchers administered CCT365623 to mice with spontaneous breast cancer, and found that the compound inhibited primary tumor growth and metastatic lung burden. Further investigation showed that CCT365623 led to a loss of EGFR on cell membranes in both primary and metastatic tumors.
In summary, the study reveals a molecular function of LOX in regulating EGFR and highlights the therapeutic potential of the LOX inhibitor CCT365623 in breast cancer. Since LOX is also implicated in several other cancers, the findings could have broad applications.
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