Abstract
Resistance to cancer therapy is a challenge because of innate tumor heterogeneity and constant tumor evolution. Since the pathway of resistance cannot be predicted, combination therapies may address this progression. We discovered that in addition to IGF1 and IGF2, IGFBP-3 binds bFGF, HGF, neuregulin, and PDGF AB with nanomolar affinity. Because growth factors drive resistance, simultaneous inhibition of multiple growth factor pathways may improve the efficacy of precision therapy. Growth factor sequestration by IGFBP-3-Fc enhances the activity of EGFR inhibitors by decreasing cell survival and inhibiting bFGF, HGF, and IGF1 growth factor rescue and also potentiates the activity of other cancer drugs. Inhibition of tumor growth in vivo with adjuvant IGFBP-3-Fc with erlotinib versus erlotinib after treatment cessation supports that the combination reduces cell survival. Inhibition of multiple growth factor pathways may postpone resistance and extend progression-free survival in many cancer indications.
Highlights
The IGF system is important in cell growth and in carcinogenesis and tumor progression of different cancer cell types[6,7]
Binding to insulin-like growth factor-1 (IGF1) and insulin-like growth factor-2 (IGF2) is consistent with published values[19,20]
Sensorgrams of HGF, NRG, and PDGF AB binding are shown in Supplementary Fig. S1, and association and dissociation constants are found in Supplementary Table S1
Summary
The IGF system is important in cell growth and in carcinogenesis and tumor progression of different cancer cell types[6,7]. IGFBP-3 exhibits an IGF-independent inhibition of proliferation and has multiple binding partners, some of which affect proteolysis[11,12,13]. We demonstrate that IGFBP-3 binds directly to multiple growth factors - bFGF, PDGF, HGF, VEGF-B, and NRG - in the nanomolar range by surface plasmon resonance and correspondingly inhibits ligand-stimulated proliferation. BFGF, EGF, HGF, IGF1, NRG, and PDGF are widely expressed in tumors[4], so the discovery of a single protein that inhibits multiple growth factors has enormous potential in cancer treatment. Inhibition of cancer cells both in vitro and in vivo This construct with multiple growth factor inhibition properties, combined with targeted therapy, may improve efficacy and postpone the development of resistance in many existing and future cancer treatments
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