ActionsCite Favorites Display options Display options Format Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer 1 Translational Research, OSI Pharmaceuticals, Inc., Farmingdale, New York 11735, USA. ebuck@osip.com Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer 1 Translational Research, OSI Pharmaceuticals, Inc., Farmingdale, New York 11735, USA. ebuck@osip.com Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. Zhao H, et al. Mol Cancer Ther. 2012 Feb;11(2):503-13. doi: 10.1158/1535-7163.MCT-11-0327. Epub 2011 Dec 9. Mol Cancer Ther. 2012. PMID: 22161861 Zinn RL, Gardner EE, Marchionni L, Murphy SC, Dobromilskaya I, Hann CL, Rudin CM. Zinn RL, et al. Mol Cancer Ther. 2013 Jun;12(6):1131-9. doi: 10.1158/1535-7163.MCT-12-0618. Epub 2013 Mar 20. Mol Cancer Ther. 2013. PMID: 23515613 Free PMC article. Buck E, et al. Expert Opin Investig Drugs. 2011 May;20(5):605-21. doi: 10.1517/13543784.2011.558501. Epub 2011 Mar 30. Expert Opin Investig Drugs. 2011. PMID: 21446886 Singh P, et al. Med Oncol. 2014 Jan;31(1):805. doi: 10.1007/s12032-013-0805-3. Epub 2013 Dec 14. Med Oncol. 2014. PMID: 24338270 Huang Y, et al. Front Cell Dev Biol. 2021 Jul 6;9:698047. doi: 10.3389/fcell.2021.698047. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 34295898 Free PMC article. Review. Crezee T, Tesselaar MH, Jaeger M, Rabold K, Corver WE, Morreau H, Van Engen-Van Grunsven ACH, Smit JWA, Netea-Maier RT, Plantinga TS. Crezee T, et al. Oncol Lett. 2021 Aug;22(2):590. doi: 10.3892/ol.2021.12851. Epub 2021 Jun 6. Oncol Lett. 2021. PMID: 34149901 Free PMC article. Rubinstein MM, et al. Br J Cancer. 2021 Apr 28. doi: 10.1038/s41416-021-01393-y. Online ahead of print. Br J Cancer. 2021. PMID: 33911195 Bleach R, et al. Front Cell Dev Biol. 2021 Mar 18;9:630503. doi: 10.3389/fcell.2021.630503. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 33816477 Free PMC article. Review.