Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy

Morgillo, Floriana; Bareschino, Maria Anna; Bianco, Roberto; Tortora, Giampaolo; Ciardiello, Fortunato

doi:10.1111/j.1432-0436.2007.00200.x

Cited by 70 publications

(69 citation statements)

References 91 publications

(92 reference statements)

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“…Currently, the two main types of therapeutics that are being applied are antibodies that bind to the EGFR extracellular domain, and small-molecule inhibitors that target its intracellular tyrosine kinase domain [2]. While efficient inhibition of EGFR with these drugs can be observed, evidence of resistance to these drugs has been described [3]. Therefore, the development of other EGFR targeting strategies is required.…”

mentioning

confidence: 99%

Escherichia coli expression and refolding of E/K-coil-tagged EGF generates fully bioactive EGF for diverse applications

Lenferink

Pinard

et al. 2009

Protein Expression and Purification

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mentioning

confidence: 99%

Escherichia coli expression and refolding of E/K-coil-tagged EGF generates fully bioactive EGF for diverse applications

Lenferink

Pinard

et al. 2009

Protein Expression and Purification

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“…Targeted therapy is a clinical reality for tumors which express EGFR (cetuximab) or HER2 (trastuzumab), although resistance has been reported in both cases (8)(9)(10)(11)(12). EGFR and HER2 appear to be good targets for radionuclide-or toxin-based tumor therapy, although whether this is the case for prostate cancer is not clear (2,3).…”

Section: Introductionmentioning

confidence: 99%

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

et al. 2012

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Abstract. The epidermal growth factor receptor (EGFR) family members are potential targets for therapy using extracellular domain receptor binding agents, such as the antibodies trastuzumab and cetuximab, or antibodies labeled with therapeutically useful radionuclides or toxins. This is especially the case when the tumor cells are resistant to chemotherapy and tyrosine kinase inhibitors. Studies concerning the expression of these receptors in prostate cancer vary in the literature, possibly due to differences in patient inclusion, sample preparations and scoring criteria. In our study, EGFR, HER2 and HER3 expression was analyzed in prostate cancer samples from primary tumors and corresponding lymph node metastases from 12 patients. The expression of HER2 and EGFR was scored from immunohistochemical preparations and the HercepTest criteria (0, 1+, 2+ or 3+), while HER3 expression was scored as no, weak or strong staining. There were 5 EGFR-positive (2+ or 3+) primary tumors and 6 EGFR-positive lymph node metastases, and there was EGFR upregulation in one metastasis. Only 4 of the 12 patients had marked HER2 expression (2+ or 3+) in their primary tumors and there was one downregulation and 5 cases of upregulation in the metastases. Thus, a total of 8 out of 12 analyzed metastases were HER2-positive. Of the 12 primary tumors, 9 expressed HER3 while only 2 of the lymph node metastases expressed recognizable HER3 staining, so 7 metastases appeared to have downregulated HER3 expression.In one of the primary tumors there was positive co-expression of EGFR and HER2, while this co-expression was observed in 4 of the metastases. Thus, there were tendencies for upregulation of HER2, increased co-expression of EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node metastases in comparison to the primary tumors. The results are encouraging for studies involving more patients. Possible strategies for EGFR-and HER2-targeted therapy are briefly discussed in the present study, especially with regard to the expression and co-expression of EGFR and HER2 in metastases.

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“…Important findings suggest that there is a strong relationship between the resistance to EGFR TKIs and the absence of an activating mutation in the intracellular kinase domain of the receptor. These EGFR kinase domain mutations, such as the point mutation, L858R, and in-frame deletion in exon 19 around codons 746-750, enhance the ligand-dependent activation of EGFR, and simultaneously increase the sensitivity to the TKIs (Han et al, 2005;Mitsudomi et al, 2005;Morgillo et al, 2007). It has also been demonstrated that the patients with the EGFR mutation-positive tumors have an improved response rate and survival after treatment with TKIs compared to the patients with tumors that express wild-type EGFR (Han et al, 2005;Mitsudomi et al, 2005).…”

Section: Resistance To the Egfr-targeted Therapiesmentioning

confidence: 89%

“…It has also been demonstrated that the patients with the EGFR mutation-positive tumors have an improved response rate and survival after treatment with TKIs compared to the patients with tumors that express wild-type EGFR (Han et al, 2005;Mitsudomi et al, 2005). Therefore, the lack of these mutations can be considered a predictor of the treatment resistance to TKI (Morgillo et al, 2007). Mechanisms contributing to the primary resistance to EGFR TKIs also include genetic alterations, for example, EGFR variant III (EGFRvIII) and activating KRAS mutations.…”

Section: Resistance To the Egfr-targeted Therapiesmentioning

confidence: 99%