Epidermal growth factor receptors (EGFRs) are a large family of receptor tyrosine kinases (TK) expressed in several types of cancer, including breast, lung, esophageal, and head and neck. EGFR and its family members are the major contributors of a complex signaling cascade that modulates growth, signaling, differentiation, adhesion, migration and survival of cancer cells. Due to their multi-dimensional role in the progression of cancer, EGFR and its family members have emerged as attractive candidates for anti-cancer therapy. Specifically the aberrant activity of EGFR has shown to play a key role in the development and growth of tumor cells, where it is involved in numerous cellular responses including proliferation and apoptosis.
Activation of EGFR signaling is triggered by ligand-induced receptor dimerization following which the tyrosine residues present in the intrinsic kinase domain of one receptor cross phosphorylates specific residues in the C-terminal tail of the partnering receptor, thus providing a scaffold for the recruitment of effector proteins. This occurs via the Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains on the effector proteins and the phosphotyrosine motif present on the intracellular tyrosine kinase domain of the receptor. On subsequent dissociation, the activated adaptor and effector proteins will further stimulate their corresponding signaling cascades, which include the KRAS-BRAF-MEKERK pathway, phosphoinositide 3-kinase (PI3K), phospholipase C gamma protein pathway, the anti-apoptotic AKT kinase pathway and the STAT signaling pathway, which leads to cell proliferation, angiogenesis, migration, survival, and adhesion. These cellular processes are often deregulated in malignant cells due to the several mutations harbored in various genes involved in these pathways.
Given the functional involvement of EGFR in diverse cellular processes, several approaches have been developed that target and interfere with EGFR mediated effects. Two distinct therapeutic approaches currently employed for targeting EGFR in various human
malignancies are the use of monoclonal antibodies and small molecule tyrosine kinase inhibitors. Each of these approaches have distinct mechanism of action; while anti-EGFR antibodies bind to extracellular domains and TK inhibitor target the intra cellular TK
domain. Recent studies have indicated the use of various chemopreventive agents in downregulating EGFR at gene level. Furthermore, several studies have substantiated and conferred significant benefits of anti-EGFR agents in several types of solid tumors including colorectal, head and neck cancer, NSCLC and pancreatic cancer in terms of overall survival, progression free survival and overall response rate.
Targeting EGFR for Cancer Therapy-Antibodies:
1) Cetuximab is an FDA approved human–murine chimeric anti-EGFR monoclonal antibody. Cetuximab binds to the second (L2) domain of EGFR thereby blocking its downstream signaling by prompting receptor internalization and encumbering ligand-receptor interaction. In 2008, the Committee for Medicinal Products for Human Use (CHMP) approved Cetuximab for patients with advanced colorectal cancer who had 75% EGFR positive expression and wild-type KRAS in their tissues and had failed oxaliplatin- or irinotecan-based chemotherapy. Cetuximab was approved by FDA in 2004 and by CHMP in 2008 in combination with platinum-based therapy for the treatment of patients with squamous cell carcinoma of the head and neck with metastatic disease and in combination with radiation therapy for locally advanced cancer.
2) is the first FDA (2006) approved human monoclonal antibody used for the treatment of EGFR-expressing metastatic colorectal cancer. It is a human monoclonal antibody specific to human EGFR, developed by immunizing transgenic mice (XenoMouse) that are capable of producing light and heavy chains of human immunoglobulin.
Targeting EGFR for Cancer Therapy-tyrosine kinase inhibitors:
1) Gefitinib is an anilinoquinazoline derived EGFR tryrosine kinase inhibitor. It is an orally active low-molecular-weight EGFR inhibitor with selective tyrosine kinase activity but does not inhibit serine-threonine kinase activity. Gefitinib is approved for the treatment of patients with NSCLC after failure of both platinum-based or docetaxel chemotherapies.
2) Erlotinib hydrochloride is another FDA-approved low molecular weight molecule similar to gefitinib, available in the form of an orally potent and selectively reversible inhibitor of EGFR tyrosine kinase. Rlotinib is currently approved in patients with relapsed NSCLC and for maintenance therapy in advanced NSCLC patients whose disease had not progressed after four cycles of platinum-based firstline chemotherapy. It is also approved for use in locally advanced, unresectable or metastatic pancreatic cancer patients in combination with a gemcitabine.
3) Multiple targeted inhibitors: Lapatinib and Canertinib can also be used to inhibit EGFR.
EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, further understanding of the system is required to develop an effective anticancer regiment. A combination therapy comprising of an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.
Seshacharyulu P, et al. Targeting the EGFR signaling pathway in cancer therapy[J]. Expert opinion on therapeutic targets, 2012, 16(1): 15-31.