A kinase-independent biological activity for insulin growth factor-1 receptor (IGF-1R): Implications for Inhibition of the IGF-1R signal

Abstract

It has been demonstrated that epidermal growth factor receptor (EGFR) can have kinase independent activity. EGFR kinase-independent function maintains intracellular glucose levels via sodium glucose transporter protein 1 (SGLT1) and supports cell survival. It is plausible that this phenomenon can apply to other receptor tyrosine kinases. We found that transfection of insulin-like growth factor receptor (IGF-1R) siRNA into HEK293 (human embryonic kidney) and MCF7 (metastatic breast cancer) cells results in decreased intracellular glucose levels, whereas treatment with the IGF-1R tyrosine kinase inhibitor OSI-906 did not affect intracellular glucose levels. In addition, IGF-1R interacted with SGLT1 in a manner similar to that previously reported with EGFR. The combination of IGF-1R siRNA and OSI-906 resulted in decreased viability of HEK293 and MCF7 cell lines compared to either agent alone. Collectively, these experiments suggest that IGF-1R, has kinase-independent biologic functions and provide a rationale for combining anti-IGF-1R antibodies or siRNA and IGF-1R small molecule inhibitors.

Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors

“…Furthermore, among the four patients who received prior bevacizumab and sorafenib sequentially, two achieved SD ≥6 months on study. Vertical inhibition of both VEGF and VEGFR using this drug combination targets both kinase-dependent and –independent pathways, a strategy that has previously demonstrated increased activity, warranting dual inhibition [5, 35]. In addition, anti-HER2 monoclonal antibody trastuzumab has demonstrated clinical synergy when given in combination with anti-HER2 tyrosine kinase inhibitor lapatinib, although a subsequent phase 3 trial did not demonstrate survival advantage with the combination [36–38].…”

Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis

“…In addition, also indirect targeting strategies, for example by inhibition of PAPP-A, a protease increasing the bioavailability of IGFs through cleavage of IGFBP4 [6], or targeting of Lin28b, an RNA regulatory protein that stimulates genes of the IGF axis [20] or enhancement of inhibition by combined targeting with the small molecule receptor kinase inhibitor OSI-906 and siRNA knockdown of IGF1R have been suggested [21]. Currently more than 100 clinical studies examining a variety of anti-IGF1R agents in several cancer entities are ongoing [22].…”

IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

“…Insulin-like growth factor 1 receptor(IGF-1R) is a transmembrane receptor tyrosine kinase mainly activated by IGF1 or IGF2 through autocrine and paracrine, which has kinase-independent biologic functions[6,7]. The activated IGF-1R binds to adaptor molecules such as insulin receptor substrates(IRSs) and Shc and then triggers multiple downstream signaling cascades, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase(MAPK) signaling pathways, which regulate oncogenic transformation, growth and survival of cancer cells[8,9].…”