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

Abstract

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

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…Supportively, Zhao et al reported that combination of CB-839 and 5-fluorouracil induced PIK3CA-mutant tumor regression in CRC xenograft models (148). Importantly, an exploratory analysis of a phase I clinical trial (NCT02861300) showed a trend of better response to combination therapy of CB-839 plus capecitabine (prodrug of 5-fluorouracil) in PIK3CAmutant CRC patients as compared to PIK3CA-WT cohort (148). More data are needed to evaluate the efficiency of glutaminase inhibition in clinical scenarios.…”

“…Nevertheless, results of CANTATA (NCT03428217) showed encouraging clinical activity and tolerability of combination therapy of CB-839 plus cabozantinib in metastatic renal cell cancer (147). Supportively, Zhao et al reported that combination of CB-839 and 5-fluorouracil induced PIK3CA-mutant tumor regression in CRC xenograft models (148). Importantly, an exploratory analysis of a phase I clinical trial (NCT02861300) showed a trend of better response to combination therapy of CB-839 plus capecitabine (prodrug of 5-fluorouracil) in PIK3CAmutant CRC patients as compared to PIK3CA-WT cohort (148).…”

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

“…The combination of the novel GLS inhibitor CB839 with the EGFR monoclonal antibody Cetuximab showed efficacy in Cetuximab-sensitive and -resistant CRC cell models, indicating that patients with refractory metastatic CRC might benefit from this combination therapy targeting both the "fuel" and signaling components required for tumor survival [267]. Additionally, the anti-tumor activity of CB839 in xenograft growth of PIK3CA-mutant CRC cells was enhanced by chemotherapeutic agent 5-fluorouracil without obvious dose-limiting toxicity, indicating the potential of the combination therapy for patients with PIK3CA-mutant colorectal cancer [268].…”

Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

“…These include telaglenastat (CB-839) [ 14 ] and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [ 13 ]. The antitumor activity of CB-839 is potentiated upon combining with conventional chemotherapeutic agents [ 15 ] and vice versa [ 16 ], suggesting the possibility of glutaminase inhibition as a novel therapeutic strategy.…”