Abstract #2809: Combination treatment with the anti-IGF1R antibody MK-0646 and the mTOR inhibitor deforolimus leads to more effective PI3K pathway targeting and anti-tumor activity

Abstract

Components of the Insulin-like Growth Factor-1 (IGF1) signaling system are over-expressed by tumors, mediating proliferation and apoptosis resistance. Targeted therapies against IGF1R are currently being tested in the clinic. To support the clinical development of a humanized antibody targeting IGF1R, MK-0646, we have investigated molecular and cellular determinants for MK-0646 response. Inhibition of IGF1R in cells with high levels of the receptor significantly blocked the AKT signaling pathway. Despite inhibition of AKT signaling by MK-0646, only modest anti-proliferative activity was observed in most cell lines in vitro. To identify enhancers of MK-0646 anti-proliferative activity, a lentiviral-mediated RNAi screen targeting 480 distinct human kinases was performed in a colon cancer cell line, HT29. shRNAs targeting multiple components of the PI3K pathway significantly (P<0.02) enhanced anti-proliferative activity of MK-0646. These results suggest that combining MK-0646 with an inhibitor of a down-stream component in the PI3K pathway may significantly enhance anti-tumor activity. mTOR is a key downstream component of the PI3K signaling pathway which regulates protein translation and metabolism. Deforolimus (AP23573; MK-8669) is an analog of Rapamycin that acts as an allosteric inhibitor of mTOR in the context of the TORC1 complex. Deforolimus is being tested clinically for the treatment of multiple tumor types. While inhibition of TORC1 by deforolimus can induce tumor growth arrest, it abrogates a negative feedback loop mediated by IRS-1, resulting in activation of AKT. A recent clinical study suggested that activation of AKT via this feedback mechanism may be associated with a shorter time-to-progression in patients treated with rapamycin (Cloughesy et al PLoS Medicine, 2008). We find that combined inhibition of TORC1 & IGF1R eliminates IRS-1 mediated feedback activation of AKT and enhances PI3K pathway inhibition. The combination of MK-0646 and deforolimus significantly enhanced anti-proliferative activity of MK-0646. Importantly, this combination demonstrated enhanced anti-tumor activity in an erlotinib-resistant, KRAS-mutant lung cancer xenograft model (A549). These results suggest that multi-node targeting of PI3K signaling via co-treatment with MK-0646 and deforolimus is a rational approach for achieving enhanced anti-tumor activity.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2809.