Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors

Thus the Bonners trial shows that cetuximab plus radiotherapy is superior to radiotherapy alone

Thus the Bonners trial shows that cetuximab plus radiotherapy is superior to radiotherapy alone. degradation (Fan et al 1994; Schlessinger 2000; Herbst and Shin 2002). EGFR is a 170-kd transmembrane glycoprotein, member of the ErbB family of tyrosine kinase receptors, composed by an extra cellular ligand-binding domain, a trasmembrane lipophilic segment and an intracellular protein kinase domain with a regulatory carboxyl terminal segment. After binding with its ligands, EGFR occurs dimerization, posphorylation of the tyrosin kinase, activating the receptor pathway, internalization and degradation (Thomson and Gill 1985; Schlessinger 2000; Carpenter and Cohen 1990; Ulrich and Schlessinger 1990; Olayioye et al 2000; Schleissinger 2000; Yarden and Sliwkowski 2001; Mendelsohn and Baselga 2003; Hynes and Lane 2005). In SCCHN the EGFR overexpression is associated with more aggressive disease, increased resistance to chemotherapy and radiotherapy, increased metastasis, inhibition of apoptosis, promotion of neoplastic angiogenesis, and, finally, poor prognosis and decreased survival (Santini et al 1991; Grandis et al 1998; Nicholson et al 2001; Ang et al 2002, 2004; Gupta et al 2002; O-Charoenrat et al 2002; Eriksen et al 2004). However, experimental studies demonstrated that the blockade of EGFR by monoclonal antibodies (Mabs) or by tyrosin- kinase inhibitors reverts radio resistance and enhances radiosensivity and chemosensivity in human SCCHN cell lines in vitro and in vivo (Goldstein et al 1995). In clinical practice, EGFR expression is evaluated using a standardized immunoistochemistry (IHC) assay, designated to asses cell membrane staining. EGFR expression is reported by the maximal intensity of the IHC stain in the cytoplasm on an ordinal scale of 0 to 3 (Goldstein et al 1995; O-Charoenrat et al 2002). Unfortunately IHC is a semi-quantitative methodology allowing wide interlab-differences. Moreover it has not yet been shown any quantitative relationship between EGFR expression and clinical response to its inhibition, so that the role of EGFR expression to predict response to EGFR targeting agents is unclear. Cetuximab and radiotherapy Robert et al (2001) evaluated a combination of escalating doses of cetuximab concurrent with radiotherapy in a phase I study. The momoclonal antibody was given from 100 to 500 mg/m2 loading dose and from 100 to 250 mg/m2 weekly maintenance dose to patients with SCCHN. Cetuximab did not worse the usual radiation therapy side effects and added only mild to moderate skin reaction. Unfortunately one patient was removed from the study, due to grade IV anaphylactic reaction. Objective responses were achieved in all the patients and AZD-5991 S-enantiomer they were complete in most cases. In conclusion Robert at al showed that cetuximab can be added to RT at the standard clinical dose (400 mg/m2 loading dose and 250/m2 weekly maintenance doses) without any dose limiting toxicity. On these bases Bonner et al (2006) conducted and published a phase III trial. In this study 424 patients with locoregional advanced head and neck cancer were randomly assigned to radiotherapy alone or the same radiotherapy plus weekly cetuximab at the standard clinical dose. The accrued patients had stage III or IV not previously treated, histologically proven, squamous cell carcinoma arising AZD-5991 S-enantiomer from oropharinx, hypopharinx and larynx. Overall 13 pts discontinued cetuximab, mostly because of hypersensitivity reactions (4 pts) or acneiform rush (8 pts). With the exception of these toxicities, the incidence of severe reactions was similar in the two treatment arms confirming that cetuximab does not exacerbate the common radiotherapy AZD-5991 S-enantiomer related side effects (Table 1). The experimental arm significantly improved loco-regional control and median survival: 24.4 months vs 14.9 (p = 0.005) and 49 vs 29.3 months (p = 0.03) respectively, compared to radiotherapy alone. Thus the Bonners trial shows that cetuximab plus radiotherapy is superior to radiotherapy alone. Interestingly, this is the first trial showing that the results of radiotherapy can be significantly improved Rabbit Polyclonal to EGFR (phospho-Ser1071) by the addition of a drug without worsening radiotherapy toxicity. Table 1 Comparison of major toxicities according to treatment plan (% of patients) thead th valign=”top” align=”left” rowspan=”1″ colspan=”1″ /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Column A br / RT cetuximaba /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Column B br / RT cisplatin cetuximabb /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Column C br / cisplatin cetuximabc /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Column D br / RT alonea /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Column E br / cisplatin + placeboc /th th valign=”top” align=”left” rowspan=”1″ AZD-5991 S-enantiomer colspan=”1″ Statistical significance /th /thead Mucositis56240520nsAcneiform rash17231610Column A vs D.