In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib

Abstract

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

“…In another recent study, Chakraborty et al . 72 have reported that treatment of MCF-7 cells with a combination of an IGF-1R mAb and the HER2 targeting agents neratinib and trastuzumab resulted in synergistic growth inhibition of these breast cancer cells, supporting the need for further investigations on the therapeutic potential of co-targeting IGF-1R and HER family members in breast cancer.…”

Mechanisms behind the Resistance to Trastuzumab in HER2-Amplified Breast Cancer and Strategies to Overcome It

“… 47 It was associated with trastuzumab resistance in a subset of 155 patients with HER2+ metastatic BCs. 24 Studies in vitro have shown synergistic effects of met-formin 48 and also of figitumumab, 49 a human mAb that blocks IGF1R ligand binding, with anti-HER2 drugs.…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…A combination of figitumumab plus the HER2-targeted therapies, trastuzumab and neratinib (HER2 TKI), was shown to elicit a synergistic effect on enhancing cell apoptosis and reducing cell proliferation in the BT474 and MCF7 breast cancer cells lines (Table 2) (Chakraborty et al 2015). Indirectly targeting IGF1R overexpression in HER2-amplified breast cancers by the introduction of miR-630 into the cell can restore the sensitivity of the cell to different HER2 inhibitors and may have clinical benefit to prevent IGF1R-driven HER2-therapy resistance (Corcoran et al 2014).…”