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

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

  • Mol Cancer. 2024 Mar 14;23(1):54. doi: 10.1186/s12943-024-01978-0.
Xin Peng # 1 2,  Xin Huang # 1 2,  Talal Ben Lulu # 3,  Wenqing Jia 1 2,  Shaolu Zhang 1 2 4,  Limor Cohen 3,  Shengfan Huang 1 2,  Jindian Fan 1 2,  Xi Chen 5 6,  Shanshan Liu 1 2,  Yongzhe Wang 1 2,  Kailin Wang 1 2,  Sho Isoyama 7,  Shingo Dan 7,  Feng Wang 8,  Zhe Zhang 9 10,  Moshe Elkabets 11,  Dexin Kong 12 13 14 15
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China.
  • 3 The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
  • 4 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
  • 5 Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China.
  • 6 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
  • 7 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
  • 8 Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 9 Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China. [email protected].
  • 10 Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China. [email protected].
  • 11 The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel. [email protected].
  • 12 Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China. [email protected].
  • 13 Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China. [email protected].
  • 14 Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, 300052, China. [email protected].
  • 15 International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China. [email protected].
  • # Contributed equally.
PMID: 38486218 DOI: 10.1186/s12943-024-01978-0
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

CD8+ T cells; Immunotherapy synergy; KTC1101; PI3K inhibitor; Tumor microenvironment.

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