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5-Fluorouracil Enhances the Anti-Tumor Activity of the Glutaminase Inhibitor CB-839 Against

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5-Fluorouracil Enhances the Anti-Tumor Activity of the Glutaminase Inhibitor CB-839 Against Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5-fluorouracil enhances the anti-tumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers Yiqing Zhao1,2,#, Xiujing Feng1,2,#, Yicheng Chen1,2,#, J. Eva Selfridge1,2,3, Shashank Gorityala4, Zhanwen Du1,2, Janet M. Wang1, Yujun Hao1,2, Gino Cioffi5, Ronald A. Conlon1,2, Jill S. Barnholtz-Sloan2,5, Joel Saltzman3,6, Smitha S. Krishnamurthi3,6, Shaveta Vinayak3,6,7, Martina Veigl2,6, Yan Xu4, David L. Bajor2,3,6, Sanford D. Markowitz2,3,6, Neal J. Meropol2,3,8, Jennifer R. Eads2,3,9*, and Zhenghe Wang1,2,* 1 Department of Genetics and Genome Sciences, 2Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106 3Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106 4Department of Chemistry, Cleveland State University, Cleveland, OH 44115 5Department of Population and Quantitative Health Sciences 6Department of Medicine, 7Department of Medicine, University of Washington, Seattle, WA 98195 8Flatiron Health, New York, NY 10013 9Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Running title: CB-839 plus 5-FU inhibit PIK3CA-mutant colon cancer growth Key Words: Colorectal cancer; PIK3CA mutation; glutaminase inhibitor; 5-fluorouracil, clinical trial. # These authors contributed equally. *Corresponding authors: Zhenghe Wang, Phone: 216-368-0446, Fax: 216-368-8919, Email: [email protected] (leading contact); Jennifer Eads, Phone: 215-615-1725, Fax: 215-349-8551, Email: [email protected] Conflict of Interest: NJM is currently an employee of Flatiron Health, Inc., an independent subsidiary of the Roche Group. NJM holds equity interests in Flatiron and Roche. JRE has a spouse employed by Bristol Myers Squibb. Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract PIK3CA encodes the p110α catalytic subunit of PI3 kinase and is frequently mutated in human cancers, including ~30% of colorectal cancer (CRC). Oncogenic mutations in PIK3CA render CRCs 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), CRCs. 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 up-regulated 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 CRC patients might derive greater benefit from this treatment strategy as compared to PIK3CA WT CRC patients. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRCs and warrants further clinical evaluation. Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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. Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction It is well documented that cancer cells in vitro can utilize glutamine as an anaplerotic substrate of the tricarboxylic acid (TCA) cycle to generate ATP and precursors for the synthesis of lipids, nucleotides and other macromolecules to sustain rapid tumor growth (1). Glutamine enters into cells by its transporter Slc1A5 (2). To enter the TCA cycle, glutamine is first converted to glutamate by glutaminases (GLSs), then to α-ketoglutarate (α-KG), a TCA cycle intermediate, by either aminotransferases or glutamate dehydrogenases (2). Our recent study shows that tumors in vivo also use glutamine as a fuel source to replenish the TCA cycle (3). In fact, targeting glutamine metabolism has shown promising results in preclinical models in a variety of tumor types including breast, kidney, lung, and pancreatic cancers, as well as acute myeloid leukemia, where all show in vivo sensitivity to the glutaminase inhibitor CB-839 (4-12). GLS1 and GLS2 are the two genes encoding glutaminases in human (13). GLS1 is expressed predominantly in kidney and cancers, whereas GLS2 is expressed in liver (13). CB-839 is a potent inhibitor of GLS1 (4). PIK3CA, which encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα) (14,15), is mutated in a wide variety of human cancers, including ~30% of colorectal cancers (CRCs) (16,17). However, an effective approach targeting PIK3CA mutations in patients with CRC is yet to be developed (18). We recently found that PIK3CA mutations render CRC cells dependent on glutamine (3,19,20). This dependency is associated with the upregulation of mitochondrial glutamate pyruvate transaminase 2 (GPT2) (19), which converts glutamate to α- Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. KG. Moreover, we demonstrated that aminooxyacetate (AOA), a pan-aminotransferase inhibitor, suppresses xenograft tumor growth of PIK3CA-mutant, but not WT, CRC (19). Here we show that CB-839 preferentially inhibits PIK3CA-mutant CRCs. Moreover, CB-839, in combination with 5-FU, induces tumor regression of PIK3CA-mutant CRCs in multiple xenograft models. These preclinical data prompted a phase I clinical trial to assess the safety and toxicity profile of a combination of CB-839 and capecitabine (an oral prodrug of 5-FU) in advanced solid tumor patients. Consistent with our preclinical data, an exploratory analysis of the clinical trial data shows a trend that CRC patients whose tumors harbor PIK3CA mutations may derive a greater clinical benefit from this treatment strategy as compared to those with PIK3CA-WT tumors. Together, the data suggest that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRC. Materials and Methods Cell culture and chemicals Colorectal cancer (CRC) cell lines, HCT116, DLD1, RKO, and SW480 were obtained from ATCC. These cell lines were cultured in McCoy’s 5A medium containing 10% fetal bovine serum, as described previously (21). The tissue culture cell lines are routinely checked for mycoplasma contamination. The cell lines were authenticated by the Genetica DNA Laboratories using STR profiling. CB-839 was kindly provided by Calithera Biosciences. Oxaliplatin, Camptothecin, and Regorafenib were purchased from Selleck Chemical. 5-Fluorouracil was purchased from Sigma-Aldrich. Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/0008-5472.CAN-20-0600 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Drug treatment of xenograft tumors Animal experiments were approved by the Case Western Reserve University Animal Care and Use Committee and performed in accordance with relevant guidelines and regulations. Subcutaneous xenografts were established as described in (22). Three million cells were injected subcutaneously into the flanks of 6 to 8-week-old female athymic nude mice. When tumors reached around 250-400 mm3, mice were randomly divided into groups (10 tumors for each group). Mice were treated with CB-839 (200 mg/kg) once or twice daily by oral gavage, 5-FU (30 mg/kg) once a day by intraperitoneal (IP) injection, or both CB-839 and 5-FU. Tumor volume was measured with electronic calipers, and volumes were calculated by the formula of length x width2/2. For PDX (patient-derived xenograft) models, tumors were first sliced into approximately 4 mm3 pieces and implanted subcutaneously into nude mice. When the average tumor volume reached around 250-400 mm3, mice were treated with the indicated drugs, and tumors were measured once per week. Flow Cytometry Cells were plated in 6-well plates at 2×105 cells per well in complete
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