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Review
. 2011 Dec;14(6):260-79.
doi: 10.1016/j.drup.2011.08.002. Epub 2011 Sep 14.

Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer

Ranee Mehra  1 , Ilya G Serebriiskii, Roland L Dunbrack Jr, Matthew K Robinson, Barbara Burtness, Erica A Golemis
Affiliations
Review

Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer

Ranee Mehra et al. Drug Resist Updat. 2011 Dec.

Abstract

Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN), antibodies targeting EGFR were the first protein-directed agents to show clinical benefit, and remain a standard component of clinical strategies for management of the disease. Nevertheless, many patients display either intrinsic or acquired resistance to these drugs; hence, major research goals are to better understand the underlying causes of resistance, and to develop new therapeutic strategies that boost the impact of EGFR/ErbB inhibitors. In this review, we first summarize current standard use of EGFR inhibitors in the context of SCCHN, and described new agents targeting EGFR currently moving through pre-clinical and clinical development. We then discuss how changes in other transmembrane receptors, including IGF1R, c-Met, and TGF-β, can confer resistance to EGFR-targeted inhibitors, and discuss new agents targeting these proteins. Moving downstream, we discuss critical EGFR-dependent effectors, including PLC-γ; PI3K and PTEN; SHC, GRB2, and RAS and the STAT proteins, as factors in resistance to EGFR-directed inhibitors and as alternative targets of therapeutic inhibition. We summarize alternative sources of resistance among cellular changes that target EGFR itself, through regulation of ligand availability, post-translational modification of EGFR, availability of EGFR partners for hetero-dimerization and control of EGFR intracellular trafficking for recycling versus degradation. Finally, we discuss new strategies to identify effective therapeutic combinations involving EGFR-targeted inhibitors, in the context of new system level data becoming available for analysis of individual tumors.

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Figures

Figure 1
Figure 1. Approaches to engineer bispecific antibodies
The modular nature of the human IgG (A) serves as the basis for engineering a variety of bsAbs. Where appropriate clinical candidates have been identified along with stage of clinical testing. B) Heterodimeric Fc. “Knobs-into-holes,” a strategy developed by Carter and colleagues (Merchant et al., 1998), uses compensatory mutations in the CH3 domain of the Fc region to favor heterodimer formation. Additional strategies that improve upon heterodimer yield and stability have recently been described. These include more comprehensive compensatory mutations (Gunasekaran et al., 2010), SEEDbodies that take advantage of chimeric CH3 domains comprised of alternating segments of IgG and IgA sequence (Davis et al., 2010), and heterodimeric rat/mouse Fc domains (Jager et al., 2009). C) Dual-specificity Fv. Fv domains capable of binding with high affinity to more than one target (Bostrom et al., 2009). D) Insertion of additional variable domains. Structures such as the Di-diabody (Lu et al., 2005), DVD-IgG (Wu et al., 2009) and IgG-scFv (Orcutt et al., 2010) rely on insertion of additional variable domains into the basic IgG format at different locations E.) Bispecific-scFv molecules. Structures that take advantage of the antigen binding properties of the scFv.
Figure 2
Figure 2. Structural consequences of EGFR mutations
A. Superposition of EGFR tyrosine kinase domain with C-SRC kinase domain. The sequence ELREA (746–750) deleted from EGFR in some head and neck cancers is shown in magenta. C-SRC has a three-residue deletion relative to wildtype EGFR in the same region, shown in orange. It loses one turn of the helix, as the ELREA mutation would be expected to do. The ATP analogue, phosphoaminophosphonic acid adenylate ester is shown in stick figure. The EGFR structure is PDB entry 2ITX (Yun et al., 2007) and the C-SRC structure is PDB entry 1K9A (Ogawa et al., 2002). B. Mutations in EGFR tyrosine kinase domain identified in HNC tumor samples. L858R is a common activating mutation in lung cancer. V765G is located on the C-helix of the N-terminal domain. K745R immediately precedes the sequence ELREA deleted in some HNC. K745 hydrogen bonds to the alpha phosphate of ATP. The structure is taken from PDB entry 2ITX.
Figure 2
Figure 2. Structural consequences of EGFR mutations
A. Superposition of EGFR tyrosine kinase domain with C-SRC kinase domain. The sequence ELREA (746–750) deleted from EGFR in some head and neck cancers is shown in magenta. C-SRC has a three-residue deletion relative to wildtype EGFR in the same region, shown in orange. It loses one turn of the helix, as the ELREA mutation would be expected to do. The ATP analogue, phosphoaminophosphonic acid adenylate ester is shown in stick figure. The EGFR structure is PDB entry 2ITX (Yun et al., 2007) and the C-SRC structure is PDB entry 1K9A (Ogawa et al., 2002). B. Mutations in EGFR tyrosine kinase domain identified in HNC tumor samples. L858R is a common activating mutation in lung cancer. V765G is located on the C-helix of the N-terminal domain. K745R immediately precedes the sequence ELREA deleted in some HNC. K745 hydrogen bonds to the alpha phosphate of ATP. The structure is taken from PDB entry 2ITX.
Figure 3
Figure 3. Homodimer of EGFR extracellular domains I-III
The variant III (EGFRvIII) deletion is colored magenta in the monomer on the left. EGF is in gray bound to both EGFR monomers. Cetuximab is in yellow. Cetuximab binding is not consistent with EGF binding or dimerization due to overlap of contacts with domain III. EGFRvIII is not likely to dimerize due to the absence of the tether loop in domain II which reaches to contact domain II of the other monomer. The EGF-bound EGFR homodimer is taken from PDB entry 1IVO (Ogiso et al., 2002) and the EGFR/cetuximab interaction is taken from PDB entry 1YY9 (Li et al., 2005b).
Figure 4
Figure 4. EGFR signaling interactions
A. Signaling downstream of EGFR family members, IGF1R and TGFβR. B. EGFR and c-MET downstream effectors. C. PI3K and PLCγ signaling downstream of EGFR. Violet, transcription factors; light blue, kinases; green, scaffolding proteins. Phosphorylation and oligomerization is only shown for EGFR/EGFR family receptors; see text for details. See for color reproduction the online version of this paper.
Figure 4
Figure 4. EGFR signaling interactions
A. Signaling downstream of EGFR family members, IGF1R and TGFβR. B. EGFR and c-MET downstream effectors. C. PI3K and PLCγ signaling downstream of EGFR. Violet, transcription factors; light blue, kinases; green, scaffolding proteins. Phosphorylation and oligomerization is only shown for EGFR/EGFR family receptors; see text for details. See for color reproduction the online version of this paper.
Figure 4
Figure 4. EGFR signaling interactions
A. Signaling downstream of EGFR family members, IGF1R and TGFβR. B. EGFR and c-MET downstream effectors. C. PI3K and PLCγ signaling downstream of EGFR. Violet, transcription factors; light blue, kinases; green, scaffolding proteins. Phosphorylation and oligomerization is only shown for EGFR/EGFR family receptors; see text for details. See for color reproduction the online version of this paper.
Figure 5
Figure 5
Signalling network integrated via scaffolding proteins NEDD9, BCAR1, and SH2D3C. See text for details. See for color reproduction the online version of this paper.
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