The insulin-like growth factor-1 receptor (IGF-1R) mediates multiple cellular responses, including activation of anti-apoptotic and proliferative pathways. Deregulation of IGF-1R through overstimulation has been associated with oncogenesis and maintenance of the transformed phenotype. IGF-1R is highly expressed in multiple solid tumor types, including breast, colorectal, lung and ovarian carcinoma, making this receptor a promising therapeutic target. We will show that IGF-1R is ubiquitously expressed in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and ovarian cancer cell lines, tumor types which have also been reported to express high levels of the epidermal growth factor receptor (EGFR). EGFR is overexpressed in 90% of HNSCC tumors and up to 77% of ovarian primary tumors, implicating these tumor types as attractive targets for EGFR blockade. Crosstalk between the EGFR and IGF-1R signaling pathways has been well described, and IGF-1R has been reported to be upregulated in cell lines which have acquired resistance to EGFR inhibition, suggesting a rationale for combining inhibitors of these receptors. Erlotinib (Tarceva®, OSI Pharmaceuticals, Inc.) is a small molecule, reversible inhibitor of EGFR which has been approved for the treatment of advanced non-small cell lung cancer and pancreatic cancer. We investigated the effects of erlotinib in combination with PQIP, a selective, small molecule inhibitor of IGF-1R. PQIP inhibited in vitro cell proliferation in a variety of HNSCC and ovarian cell lines, including several which are insensitive to erlotinib. We will present how inhibition of the IGF-1R signaling pathway can directly inhibit proliferation of HNSCC and ovarian tumor cell lines as well as increase the effectiveness of EGFR inhibitors in these tumor types. The combination of erlotinib and PQIP showed greater maximal growth inhibition than either compound alone. Most notably, the combination of PQIP and erlotinib was at least additive in all cell lines tested and synergistic in the majority. The combination of erlotinib and PQIP also induced apoptosis in tumor cell lines where either compound alone did not. Furthermore the combination of these inhibitors reduced phosphorylation of AKT to a greater degree than either drug alone. The molecular basis for the additive versus synergistic effect of this combination was also investigated. The effects of these molecular targeted agents on downstream signaling effectors including AKT, ERK and S6 will be presented. Together, the data suggest that the combination of erlotinib and a small molecule inhibitor of IGF-1R may be an effective strategy for treatment of head and neck and ovarian cancers.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA