Unliganded Epidermal Growth Factor Receptor Dimerization Induced by Direct Interaction of Quinazolines with the ATP Binding Site

Abstract

(11,12), suggesting a more than passive role of the IC domain in dimerization.The requirement for the EGFR tyrosine kinase activity in cellular signaling is based upon observations that receptors in which Lys-721 within the ATP binding site has been mutated and, hence, lack detectable kinase activity, do not display the full range of biochemical responses (13-15). This apparent requirement for kinase activity has focused attention on the development of drugs capable of blocking kinase activity specifically. Quinazoline inhibitors of the EGFR kinase are competitive with ATP; in the 1-10 nM range, they block EGFR phosphorylation and Src kinase activity in vivo but do not inhibit the platelet-derived growth factor receptor, p210Bcr-Abl , insulin receptor, CSF-1 receptor, and bFGF receptor tyrosine kinases (16 -19). In studying the ability of the EGFR kinase quinazoline inhibitors AG-1478 and AG-1517 to block TGF␣-induced signaling, their effect on receptor dimerization was measured. These studies demonstrated that quinazoline inhibitors per se induce inactive EGFR homodimers in EGFR-overexpressing cells or EGFR/ErbB-2 heterodimers in cells overexpressing ErbB-2 and containing lower levels of EGFR. The ability of the quinazolines to inhibit kinase function by sequestering receptors into inactive dimers appears related to their interaction with the receptor ATP binding site. These data suggest a novel biochemical mechanism of (inactive) receptor dimerization in which the initial monomer interactions are

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

“…It is thus of major interest that several quinazoline-based chemicals have been demonstrated to compete with ATP binding to protein tyrosine kinases to inhibit various intracellular signalling pathways (Rewcastle et al, 1995). The mechanism of action for quinazoline-based TKI involves prevention of the transmembrane tyrosine kinase phosphorylation by competing with the ATP-binding site on the receptor (Arteaga et al, 1997). The presence of this component may provide additional valuable insights into the molecular mechanisms for a1-adrenoceptor antagonist-mediated apoptotic action in tumour cells (Anglin et al, 2002).…”

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…Addition of anti-EGFR antibodies would improve the efficacy of TKIs, as it would keep the receptor inactive once the TKIs disassociate. This model provides a possible explanation for the efficacy of the combination of TKIs with anti-EGFR antibodies, especially in conditions when the ligands are present in limiting amounts (Arteaga et al, 1997;Lichtner et al, 2001;Gan et al, 2007). Besides the enhanced receptor stability, it is possible that the increased receptor number could also play a role in the observed enhanced co-immunoprecipitation of EGFR or HER3 with HER2.…”

“…Inactive EGFR/ HER dimers also occur after therapy with EGFR TKIs (Anido et al, 2003). The binding of these agents to the ATP pocket of the receptor perturbs its three-dimensional structure, stabilizing interactions among receptors and promoting the accumulation of inactive EGFR dimers (Arteaga et al, 1997;Gan et al, 2007). The presence of high levels of EGFR inactive dimers on the cell surface would also act as a ligand trap, being able to bind (and sequester) the ligands without consequent receptor phosphorylation.…”

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs): Simple drugs with a complex mechanism of action?

“…These observations clearly suggest that the activity of ZD1839 on ErbB-2 phosphorylation is mediated by the EGFR. Interestingly, Arteaga et al (1997) have previously shown that quinazoline EGFR-TKIs induce the formation of EGFR/ErbB-2 heterodimers in SK-Br-3 cells even in the absence of ligands. Experimental data suggest that treatment with ZD1839 also affects ErbB-3 signaling.…”