2. Academic Validation
  3. Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer

Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer

  • Oncogene. 2020 Apr;39(14):3028-3040. doi: 10.1038/s41388-020-1202-y.
Sean P Kennedy 1,  Michael O'Neill 2,  Darren Cunningham 2,  Patrick G Morris 3 4,  Sinead Toomey 3,  Carmen Blanco-Aparicio 5,  Sonia Martinez 5,  Joaquin Pastor 5,  Alex J Eustace # 6,  Bryan T Hennessy # 3 4 7
Affiliations

Affiliations

  • 1 Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons Ireland, Smurfit Building Beaumont Hospital, Beaumont, Dublin, Ireland. Seanpkennedy@rcsi.ie.
  • 2 Inflection Biosciences, Anglesea House, Blackrock, Dublin, Ireland.
  • 3 Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons Ireland, Smurfit Building Beaumont Hospital, Beaumont, Dublin, Ireland.
  • 4 Cancer Clinical Trials and Research Unit, Beaumont Hospital, Dublin, Ireland.
  • 5 Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 6 Molecular Therapeutics for Cancer in Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
  • 7 Cancer Trials Ireland, Innovation House, Old Finglas Road, Botanic, Dublin, Ireland.
  • # Contributed equally.
PMID: 32042115 DOI: 10.1038/s41388-020-1202-y
Abstract

The proviral integration of Moloney virus (Pim) family of protein kinases are overexpressed in many haematological and solid tumours. Pim kinase expression is elevated in PI3K inhibitor-treated breast Cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast Cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both Pim and PI3K/Akt/mTOR signalling. We thus evaluated the preclinical activity of IBL-302, in a range of Breast Cancer Models. Our results demonstrate in vitro efficacy of IBL-302 in a range of breast Cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. IBL-302 demonstrated single-agent, anti-tumour efficacy in suppression of pAKT, pmTOR and pBAD in the SKBR-3, BT-474 and HCC-1954 HER2+/PIK3CA-mutated cell lines. We have also shown the in vivo single-agent efficacy of IBL-302 in the subcutaneous BT-474 and HCC-1954 xenograft model in BALB/c nude mice. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast Cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel Pim and PI3K/mTOR Inhibitor, IBL-302, represents an exciting new potential treatment option for breast Cancer, and that it should be considered for clinical investigation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157169
    98.21%, PIM/PI3K/AKT/mTOR抑制剂
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