Integration of EGFR inhibitors with radiochemotherapy

Abstract

Laboratory studies that led to the development of epidermal growth factor receptor (EGFR) inhibitors indicated that such inhibitors would be effective when given to patients with tumours that are driven by activated EGFR. However, initial clinical studies have shown modest responses to EGFR inhibitors when used alone, and it has not yet been possible to clearly identify which tumours will respond to this therapy. As a result, EGFR inhibitors are now used in combination with radiation therapy, chemotherapy and, more recently, with concurrent radiochemotherapy. In general, these clinical trials have been designed without much preclinical data. What do we need to know to make these combinations successful in the clinic?

The contribution of targeted therapy to the neoadjuvant chemoradiation of rectal cancer

“…The G1 cell cycle arrest caused by cetuximab reduces the radiosensitizing activity of fluoropyrimidines, oxaliplatin or irinotecan, mainly exerted in the S/G2/M phases [20]. These negative interactions are overcome by delivering cytotoxics before EGFR inhibitors [88]. These suggestions have been confirmed by in vivo studies [89] and ongoing clinical trials are evaluating these new sequences [73].…”

The EGFR demonstrates linear signal transmission

“…8 At the same time, ligand binding perturbs the balance of the individual receptor trafficking processes by increasing the internalization rate of the EGFR. 9,10 Via this mechanism, receptor activation can potentially exert a negative feedback effect by increasing internalisation, and eventually degradation, of receptors and ligands in lysosomes. 1,11,12 A number of mathematical models for the EGFR system have shed new light on the design principles underpinning growth factor signalling.…”

Radiotherapy and inhibition of the EGF family as treatment strategies for prostate cancer: combining theragnostics with theragates

“…Multiple evidences indicate that elevated EGFR expression is an important determinant of radiation response and that EGFR exhibits a radioprotective function [16,18,20,21]. The radiation resistance is mainly thought to occur due to the activation of signaling cascades leading to tumor cell Fig.…”

“…The newly phosphorylated tyrosine residues act as docking sites for intracellular signaling molecules, which further induce different downstream signaling pathways, dependent on the receptor pair combination. These pathways include the Ras-Raf-mitogen-activated protein kinase (MAPK) cascade, the phosphoinositide 3-kinase (PI3K)-Akt cascade, the Janus kinase (JAK) and the signal transducer and activator of transcription (STAT) cascade, as well as the protein kinase C (PKC) cascade [13,16,17]. Figure 3 illustrates some of the complex signaling interactions derived from EGF receptors.…”

“…Further, activation of EGFR signaling has been reported to be mediated by ionizing radiation. Thus, exposure of EGFR overexpressing tumor cells to ionizing radiation is expected to activate survival and proliferation mechanisms predominantly through PI3K-Akt and Ras-Raf-MAPK signaling pathways, which subsequently inhibits apoptosis and promotes cell proliferation and repopulation [16,18,19]. As a consequence, activation of these two pathways is thought to be the main causes of radiotherapy resistance of EGFR overexpressing tumors [16,18,20,21].…”