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

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.