Metabolic isozyme targets in cancer

Metabolic reactions in normal cells are often catalyzed by multiple isozymes having similar or identical substrate specificities but different kinetic characteristics or tissue specificity. Metabolic reprogramming is a cancer hallmark and could occur through loss of isozyme diversity (LID) resulting in dependence on a single cancer-dominant isozyme. We examined 1,341 enzymatic reactions that involved human proteins and investigated the prevalence of LID in 14 cancer types. About 5-30% of isozymes were differentially expressed in cancer compared to corresponding normal tissues. We identified 357 enzymatic reactions that demonstrated LID in at least one cancer type and the most common, Acetyl-CoA carboxylase (ACACA), was found as the cancer-dominant isozyme in 12 cancer types. Seventeen percent of isozymes showing LID were critical for cell proliferation in the corresponding cancer types after gene knockout indicating therapeutic target potential. We further characterized the therapeutic potential of a small molecule inhibitor of ACACA that catalyzes the initial rate limiting step of de novo fatty acid synthesis and showed that it inhibits the growth of a broad range of breast cancer in cell lines in vivo, and in mouse xenograft and PDX models.