Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

• Published in: Cancer letters Vol. 442; pp. 91 - 103
• Main Authors: De Vera, Albert A., Gupta, Pranav, Lei, Zining, Liao, Dan, Narayanan, Silpa, Teng, Qiuxu, Reznik, Sandra E., Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.02.2019; Elsevier Limited
• Subjects: ABC transporters; ABCB1 transporter; Adenosine triphosphatase; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B - agonists; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Binding Sites; Cancer; Cancer immunotherapy; Cancer therapies; Chemotherapy; Class Ib Phosphatidylinositol 3-Kinase - chemistry; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Clinical trials; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Combination chemotherapy; Cytotoxicity; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drugs; Genotype & phenotype; Glycoproteins; Humans; Immune checkpoint; Immunogenicity; Immunotherapy; IPI-549; Kinases; LLC-PK1 Cells; Localization; Male; MDR1 protein; Mice, Nude; Molecular Docking Simulation; Monoclonal antibodies; Multidrug resistance; Multidrug resistant organisms; Neoplasm Proteins - metabolism; P-Glycoprotein; Paclitaxel; Paclitaxel - metabolism; Paclitaxel - pharmacology; PD-1 protein; Penicillin; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; Protein Conformation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Signal Transduction - drug effects; Swine; Targeted cancer therapy; Tumors; Xenograft Model Antitumor Assays; Xenografts; United States > US; BCRP; ABC; MDSC; P-gp; NSCLC; ABCB1 transporter; Multidrug resistance; Tregs; ICB; IPI-549; ICD; PI3Kγ; TME; P-glycoprotein; Immune checkpoint; Combination chemotherapy; TAA; PD-L1; CTLA-4; CTL; TNBC; NK; PD-1; DC
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.10.020

Phosphoinositide 3-kinase gamma isoform (PI3Kγ) plays a critical role in myeloid-derived cells of the immunosuppressive tumor microenvironment. IPI-549, a recently discovered small molecule selective PI3Kγ inhibitor, is currently under immuno-oncology clinical trials in combination with nivolumab, an anti-PD-1 monoclonal antibody immune checkpoint blocker. The purpose of this study is to investigate whether IPI-549 could reverse P-glycoprotein (P-gp)-mediated MDR when combined with chemotherapeutic substrates of P-gp. Cytotoxicity assays showed that IPI-549 reverses P-gp-mediated MDR in SW620/Ad300 and LLC-PK-MDR1 cells. IPI-549 increases the amount of intracellular paclitaxel and inhibits the efflux of paclitaxel out of SW620/Ad300 cells. ABCB1-ATPase assay showed that IPI-549 stimulates the activity of ABCB1-ATPase. IPI-549 does not alter the expression and does not affect the subcellular localization of P-gp in SW620/Ad300 cells. The combination of IPI-549 with paclitaxel showed that IPI-549 potentiates the anti-tumor effects of paclitaxel in P-gp-overexpressing MDR SW620/Ad300 xenograft tumors. With clinical trials beginning to add newly approved immune checkpoint-based immunotherapy into standard-of-care immunogenic chemotherapy to improve patient outcomes, our findings support the rationale of adding IPI-549 to both the chemotherapeutic and immunotherapeutic aspects of cancer combination treatment strategies. [Display omitted] •IPI-549 sensitizes multidrug resistant cancer (MDR) cells to P-glycoprotein chemotherapeutic substrate drugs.•IPI-549 increases the intracellular concentration and inhibits the efflux of paclitaxel by P-glycoprotein.•IPI-549 stimulates ABCB1-ATPase activity as a competitive substrate of P-glycoprotein.•IPI-549 potentiates paclitaxel against P-glycoprotein-mediated MDR in a mouse tumor xenograft model.