Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

Abstract

Background:Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways.Methods:Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR.Results:IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration.Conclusions:IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies.

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

“…It has also been shown that high ERβ is expressed in TNBC and associated with worse prognostic outcomes (Hamilton et al 2015). A combination therapy comprising the IGF-2 sequestering antibody MAB292 and topotecan to inhibit the hypoxia-inducible factor-1 enhances the anti-migratory effect of NVP-AEW541 in the TNBC MDA-MB-231 cell line (Mancini et al 2014).…”

Co-Targeting IGF-1R and Autophagy Enhances the Effects of Cell Growth Suppression and Apoptosis Induced by the IGF-1R Inhibitor NVP-AEW541 in Triple-Negative Breast Cancer Cells

“…Insulin-like growth factor-1 (IGF-1) signaling is associated with various types of cancers, including pancreatic, lung and breast cancers [13–15]. Activation of IGF-1 receptor (IGF-1R) by IGF-1 binding results in cell proliferation, metastasis and drug resistance, and it is reported that IGF-1R promotes survival and proliferation of TNBC cell lines [16].…”

“…Activation of IGF-1 receptor (IGF-1R) by IGF-1 binding results in cell proliferation, metastasis and drug resistance, and it is reported that IGF-1R promotes survival and proliferation of TNBC cell lines [16]. In fact, targeting IGF-1R inhibited migration and invasion of the TNCB cell line MDA-MB-231 [15]. Furthermore, in vivo experiments have shown that IGF-1R knockdown reduced the potential of MDA-MB-231 cells to establish brain metastases [17].…”

The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

“…Along similar lines ALK/IGF1R inhibition was recently described as a new therapeutic approach for lung cancer [77]. Furthermore preclinical studies using cancer cell lines strongly support the rationale for co-targeting IGF1R and HIF1 in breast cancer [78] or IGF1R and c-kit in non-small cell lung cancer [79]. Moreover, treatment of CRPC using a combination of IGF axis inhibitors with new generation AR inhibitors, or with other targeting drugs, awaits evaluation in preclinical and clinical studies.…”