5-Fluorouracil Enhances the Antitumor Activity of the Glutaminase Inhibitor CB-839 against PIK3CA-Mutant Colorectal Cancers

摘要: PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% colorectal cancer. Oncogenic mutations render cancers more dependent on glutamine. Here we report that glutaminase inhibitor CB-839 preferentially inhibits xenograft growth PIK3CA-mutant, but not wild-type (WT), cancers. Moreover, combination 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression models. treatment increased reactive oxygen species caused nuclear translocation Nrf2, which turn upregulated mRNA expression uridine phosphorylase 1 (UPP1). UPP1 facilitated conversion 5-FU to its active compound, thereby enhancing inhibition thymidylate synthase. Consistently, knockout abrogated inhibitory effect combined administration. A phase I clinical trial showed capecitabine, a prodrug 5-FU, was well tolerated at biologically-active doses. Although designed test efficacy, an exploratory analysis data trend patients with cancer might derive greater benefit from this strategy as compared WT These results effectively demonstrate targeting glutamine metabolism may be effective approach for treating warrants further evaluation. SIGNIFICANCE: Preclinical suggest capecitabine could serve