A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation

Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, rest...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular cancer Vol. 23; no. 1; p. 54
Main Authors:	Peng, Xin, Huang, Xin, Lulu, Talal Ben, Jia, Wenqing, Zhang, Shaolu, Cohen, Limor, Huang, Shengfan, Fan, Jindian, Chen, Xi, Liu, Shanshan, Wang, Yongzhe, Wang, Kailin, Isoyama, Sho, Dan, Shingo, Wang, Feng, Zhang, Zhe, Elkabets, Moshe, Kong, Dexin
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 14-03-2024 BioMed Central BMC
Subjects:	1-Phosphatidylinositol 3-kinase Acute toxicity Analysis Animal models Antibodies Bioavailability Cancer Cancer therapies Care and treatment CD8 antigen CD8+ T cells Cell cycle Cell growth Cell proliferation Chemical synthesis Development and progression Enzyme-linked immunosorbent assay Ethylenediaminetetraacetic acid Flow cytometry Health aspects Immunohistochemistry Immunotherapy Immunotherapy synergy Kinases KTC1101 Lymphocytes T Mass spectroscopy Metastases Molecular modelling NMR Nuclear magnetic resonance PD-1 protein Pharmacokinetics PI3K inhibitor Prevention Proteins RNA RNA sequencing Signal transduction Software T cells Tumor cell lines Tumor microenvironment Tumor suppression Tumors Xenografts Immunotherapy synergy CD8+ T cells KTC1101 Tumor microenvironment PI3K inhibitor
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models. KTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC-MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR. KTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8 T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models. KTC1101's dual mechanism of action-directly inhibiting tumor cell growth and dynamically enhancing the immune response- represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1476-4598 1476-4598
DOI:	10.1186/s12943-024-01978-0