Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations - PubMed (original) (raw)

Review

Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations

Jill Wykosky et al. Chin J Cancer. 2011 Jan.

Abstract

Epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in human cancer by way of over-expression, amplification, and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation, and resistance to apoptosis. Small molecule tyrosine kinase inhibitors and monoclonal antibodies are among the most common EGFR-targeting agents and have been used clinically for treating various malignancies. This review discusses the successes and challenges of targeting EGFR in human cancer. The genetic alterations of EGFR tend to occur more often in some solid tumors than others, as do the mechanisms of resistance to targeted inhibition. The clinical and basic science experiences with these agents thus far have important implications for the future of therapeutic targeting of EGFR.

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Figures

Figure 1.

Figure 1.. Structural organization, signaling properties, and cancer-associated mutations of epidermal growth factor receptor (EGFR). The domain structure of EGFR is shown, together with the locations of the domain boundaries: L1 and L2, ligand-binding domains 1 and 2; CR1 and CR2, cysteine-rich domains 1 and 2. The major autophosphorylation sites on EGFR, together with the docking proteins and enzymes that are known to associate with these sites to nucleate downstream signaling pathways are shown,. Activation of PI3K/Akt signaling by EGFR homodimers is largely driven by recruitment of the p85 regulatory subunit to the Gab1 adaptor protein that binds to Grb2. Along with Shc, Grb2 also mediates activation of Ras signaling by recruitment of the guanine nucleotide exchange factor, SOS. The kinase domain mutations documented in non-small cell lung cancer (NSCLC) and deletion mutations found in glioblastoma (GBM) are detailed, with the most frequent alterations (L858R and ΔEGFR/EGFRvlll respectively) shown in bold ,. The T790M “_gatekeeper mutation_” is associated with acquired resistance to Erlotinib in NSCLC (see text for details and further references).

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