Heterogeneity of Receptor Function in Colon Carcinoma Cells Determined by Cross-talk between Type I Insulin-like Growth Factor Receptor and Epidermal Growth Factor Receptor

Abstract

This study identifies a novel crosstalk paradigm between the IGF1R and EGFR in colon cancer cells. IGF1R activation by ligand exposure in growth factor deprived cells induces Akt activation in the FET, CBS and GEO colon cancer cell lines. Investigation of IGF1R mediated signaling pathways using siRNA approaches indicated that, as expected, PI3K was activated by IGF1R. MAPK activity as reflected by phospho-Erk induction was not significantly activated until later times following release of these cells from growth factor deprivation stress. The appearance of phospho-Erk was proximal to EGFR activation. Treatment of cells with the PI3K inhibitor LY294002 prior to release from stress resulted in a concentration dependent loss of EGFR activation while treatment with the MAPK inhibitor PD98059 did not block EGFR activation indicating that EGFR activation was downstream of the IGF1R/PI3K pathway. PD98059 inhibition of MAPK was associated with a concentration dependent reduction in EGFR-mediated phospho-Erk. EGFR inhibitor blocked induction of phospho-Erk showing that MAPK activity was a consequence of EGFR mediated signaling. On the other hand, a small molecule IGF1R inhibitor, PQIP, blocked Akt phosphorylation. The divergent signaling functions of IGF1R and EGFR suggested the potential for synergism by a combination of therapy directed at the 2 receptors. Combination treatment with PQIP and EGFR inhibitor Tarceva resulted in synergistic effects as indicated by combination index analysis in all 3 cell lines tested.

Gene silencing of BAG-1 modulates apoptotic genes and sensitizes lung cancer cell lines to cisplatin-induced apoptosis

“…26 Other studies have described IGF1R-mediated activation of EGFR through induction of an autocrine TGFa loop. 27,28 Unexpectedly, in the current study, mRNA levels of TGFa were decreased, while those of IGF1R increased. Activation of IGF1R did not upregulate EGFR.…”

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

“…22 Therefore, simultaneous blockade of both EGFR and IGF-IR signaling has the potential to improve clinical efficacy in tumors driven by both receptors, by limiting the development of EGFR or IGF-IR resistance from cross-talk between the two signaling pathways. 2,23 Our results demonstrate that the bispecific EI-Tandem blocked the function of EGFR and IGF-IR in in vitro cell-based assays and exhibited antitumor activity in nude mouse models where growth is driven by EGFR or IGF-IR.…”

“…The clarified lysate was purified using a Ni-NTA Superflow matrix column (Qiagen ® ) with standard washing and elution methods. 23 To allow for PEGylation, the protein was modified near the C-terminus by a serine to cysteine mutation. PEGylation of the protein was accomplished by incubating maleimidederivatized PEG reagent with the protein solution.…”

Pharmacodynamic Modeling of Sequence-Dependent Antitumor Activity of Insulin-like Growth Factor Blockade and Gemcitabine

“…The phosphorylated adaptor proteins then serve as docking sites for other signaling molecules, resulting in the activation of the downstream pathways such as phosphatidylinositol 3′-kinase (PI3K) and the mitogen-activated protein kinase (MAPK). Both PI3K and MAPK influence key cell survival and proliferation events (4)(5)(6)(7). IGF-1R has also been shown to mediate cell cycle reentry from a quiescent state through the induction of transforming growth factor α-mediated activation of epidermal growth factor receptor (5).…”