Cancer Therapeutics Insights ATPCitrate LyaseMediates Resistance of Colorectal Cancer Cells to SN38

Combination chemotherapy is standard for metastatic colorectal cancer; however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in firstand second-line therapy for patients with metastatic colorectal cancer, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in colorectal cancer comparedwith its levels in normalmucosa and in chemoresistant colorectal cancer cells comparedwith isogenic chemo-na€ ve colorectal cancer cells. Overexpression of exogenousACLy by lentivirus transduction in chemo-na€ ve colorectal cancer cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown ofACLy by siRNAor inhibition of its activity by a small-molecule inhibitor sensitized chemo-na€ ve colorectal cancer cells to SN38. Furthermore, ACLywas significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-na€ ve cells, targeting ACLy alone was not effective in resensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition ofAKT signaling andACLy successfully resensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance.Mol Cancer Ther; 12(12);