Other Strategies to Target EGFR function

Other classes of compounds to target various aspects of EGFR biology and biochemistry have been proposed. Clinically, EGFR over-expression can occur in NSCLC upon treatment with EGFR TKIs and this may represent an acquired resistance mechanism. Certain compounds such as vitamin D and retinoic acid, which promote changes in gene expression via ligation of steroid-like nuclear receptors, can cause decreased EGFR gene transcription due to the presence of response elements in the promoter region of the gene (100,101). Thus, vitamin D and retinoic acid analogues could be used to reduce EGFR expression in NSCLC where long-term treatment with EGFR TKIs has lead to its over-expression.

Another potential "Achille's heel" for mutant EGFR proteins, which it shares with several other oncoproteins, is that it requires the activity of chaperone proteins such as hsp90 to maintain a correct tertiary fold (102). In the absence of hsp90 activity, EGFR becomes misfolded and is rapidly degraged via the ubiquitin/proteosome machinery. Geldanamycin, an ansamycin antibiotic, can potently block the activity of the ATP-dependent hsp90 and has been shown to facilitate the rapid degradation of mutant EGFR in NSCLC cell lines harboring such mutants, including NCI-H1975, which harbors a T790M TKI-resistance mutation (102). Thus, geldanamycin or its derivatives may be useful agents in the treatment of NSCLC patients that have become refractory to EGFR TKIs.

A mechanism by which ErbB receptor ligands can be released to engender ErbB activation, is via proteolytic cleavage of cell-surface tethered proligands (103). This is mediated by extracellular matrix metalloproteases, such as those belonging to the ADAM family. In some gefitinib-resistant NSCLC cell lines, it appears that an autocrine signaling loop involving the proteolytic release of heregulin by the ligand sheddase ADAM-17 leads to ErbB2/ErbB3 hyperactivation (104). Thus, an ADAM inhibitor, INCB3619 can inhibit ErbB signaling in these cell lines and sensitize them to growth inhibitory effects of gefitinib. Such studies have not been validated in vivo but may provide some promise as a means to target EGFR in the 90% of NSCLC cases that are unresponsive to gefitinib.

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