Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities

Abstract

Aberrant expression of the epidermal growth factor receptor (EGFR) system has been reported in a wide range of epithelial cancers. In some studies, this has also been associated with a poor prognosis and resistance to the conventional forms of therapies. These discoveries have led to the strategic development of several kinds of EGFR inhibitors, five of which have gained US Food and Drug Administration approval for the treatment of patients with non-small-cell lung cancer (gefitinib and erlotinib), metastatic colorectal cancer (cetuximab and panitumumab), head and neck (cetuximab), pancreatic cancer (erlotinib) and breast (lapatinib) cancer. Despite these advances and recent studies on the predictive value of activating EGFR mutation and KRAS mutations with response in non-small-cell lung cancer and colon cancer patients, there is currently no reliable predictive marker for response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab or the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib. In particular, there has been no clear association between the expression of EGFR, determined by the US Food and Drug Administration-approved EGFR PharmDX kit, and response to the EGFR inhibitors. Here, we discuss some of the controversial data and explanatory factors as well as future studies for the establishment of more reliable markers for response to therapy with EGFR inhibitors. Such investigations should lead to the selection of a more specific subpopulation of cancer patients who benefit from therapy with EGFR inhibitors, but equally to spare those who will receive no benefit or a detrimental effect from such biological agents.

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

“…The involvement of EGFR activation in a number of cellular pathways promoting tumorigenesis may explain the benefit from the recently implemented anti-EGFR therapies (i.e., cetuximab or panitumab) (3,7,8). Nonetheless, the prognostic and predictive value of EGFR status in CRC remains uncertain (3).…”

“…Activation of EGFR promotes carcinogenesis, by increasing proliferation, cell migration, angiogenesis and apoptosis inhibition (4-6). On this basis, targeted therapies using anti-EGFR antibodies and tyrosine-kinase inhibitors are now an approved treatment in metastatic CRC (7,8). However, immunohistochemically assessed EGFR expression has not been validated as a predictor of response to this specific treatment.…”

Growth response of human colorectal tumour cell lines to treatment with afatinib (BIBW2992), an irreversible erbB family blocker, and its association with expression of HER family members

“…The binding of ligands to the external domain of EGFR leads to the formation of homo-or heterodimers with members of this family. Transphosphorylation of several tyrosine residues in the intracellular domain of these receptors leads to the activation of multiple downstream signaling pathways, including the ras/raf/MAPK, JAK-STAT and the PI-3/Akt pathways (8,9). The biological consequences of aberrant erbB receptor family activation in human malignancies include: Increased cell proliferation, reduced apoptosis, increased angiogenesis, increased motility, invasion and metastasis which are the hallmarks of human cancers (9,10).…”

“…However, while these agents in combination with standard chemotherapy improve the survival of CRC cancer patients, the duration of response is often limited. In addition, no clear association has been reported between the expression of EGFR in CRC and response to the EGFR inhibitors (9). In some studies, the expression of other growth factor receptors (e.g., HER-2, HER-3 and IGF-IR), EGFR gene amplification, the presence of somatic EGFR mutations in exons 18 to 21, mutations of KRAS or PTEN, and the amplification of MET or the expression of autocrine growth factors (e.g., TGFα, amphiregulin) have been suggested as indicators of response or resistance to therapy with the EGFR inhibitors (9,10,(16)(17)(18)(19).…”

21st International Congress on Anticancer Treatment

“…Ongoing large academic and industrial clinical trials are now investigating, in the particular scope of breast cancer patients, the potential benefits of new targeted therapies, including ErbB and tyrosine kinase inhibitors, and antiangiogenics [2]. First results demonstrated high efficacy of these drugs nevertheless counterbalanced by the growing clinical and biological evidence that tumor cells may develop unexpected and complex mechanisms of resistance [3].…”