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

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.

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC

“…A large number of studies link PIM1 activity to a more invasive tumor phenotype and worse prognosis in cancers [ 19 , 20 , 21 , 22 , 23 ]. Thus, the PIM kinase pathway has become an attractive target for cancer therapy with a number of drugs under investigation in the clinic including TP-3654 in advanced solid tumors (NCT03715504) and myelofibrosis (NCT04176198) and PIM447 in myelofibrosis (NCT02370706) as well as a number of drugs at preclinical stages of testing [ 11 , 24 , 25 , 26 ]. Here we show that all three PIM kinases are expressed in HCC827, H460 and H1975 cell lines and PIM1 positive NSCLC patients had a worse median survival than those that were PIM1 negative ( p = 0.056).…”

Systems pharmacology in combination with proteomics reveals underlying mechanisms of Xihuang pill against triple-negative breast cancer

“…Of the signaling pathways, PI3K-AKT was the most significantly enriched signaling pathway, which was frequently activated in patients with TNBC. The pathway was considered as a promising therapeutic target, and several inhibitors targeting this pathway were designed and evaluated in various clinical trials [61,[63][64][65]. More importantly, these findings confirmed that TCM exhibits synergistic effects against diseases through multiple-ingredient, multiple-target, and multiple-pathway approaches [9,10,23,30].…”

The miR-1185-2-3p—GOLPH3L pathway promotes glucose metabolism in breast cancer by stabilizing p53-induced SERPINE1

“…Approximately 2 of 3 breast cancers are hormone receptor-positive (ER+ or PR+). Treatment with hormone therapy is often helpful in these cases, and certain targeted therapy drugs, such as CDK4/6 inhibitors [ 13 ], mTOR inhibitor (Everolimus) and PI3K inhibitor (Alpelisib) [ 38 ], can increase the efficacy of hormone therapy. Among all types of breast cancer, triple-negative breast cancer (TNBC) has the worst prognosis due to the lack of an effective target.…”