Expression of Oncogenic Epidermal Growth Factor Receptor Family Kinases Induces Paclitaxel Resistance and Alters β-Tubulin Isotype Expression

Abstract

Oncogenic transformation confers resistance to chemotherapy through a variety of mechanisms, including suppression of apoptosis, increased drug metabolism, and modification of target proteins. Oncogenic epidermal growth factor receptor family members, including EGFRvIII and HER2, are expressed in a broad spectrum of human malignancies. Cell lines transfected with EGFRvIII and HER2 are more resistant to paclitaxelmediated cytotoxicity, and tubulin polymerization induced by paclitaxel is suppressed compared with cells expressing wild type epidermal growth factor receptor. Because differential expression of ␤-tubulin isotypes has been proposed to modulate paclitaxel resistance, we analyzed ␤-tubulin isotypes expressed in cell lines transfected with different oncogenes. EGFRvIII-and HER2-expressing cells demonstrated equivalent total ␤-tubulin protein compared with cells transfected with wild type receptor or untransfected controls. EGFRvIII-expressing cells demonstrated increases in class IVa (2.5-fold) and IVb (3.1-fold) mRNA, and HER2-expressing cells showed increases in class IVa (2.95-fold) mRNA. Expression of oncogenic Ha-Ras did not change class IV RNA levels significantly. Inhibition of EGFRvIII kinase activity using a mutant allele with an inactivating mutation in the kinase domain decreased expression of class IVa by 50% and partially reversed resistance to paclitaxel. Expression of oncogenic epidermal growth factor receptor family members is associated with modulation of both ␤-tubulin isotype expression and paclitaxel resistance in cells transformed by expression of the receptor. This effect on tubulin expression may modulate drug resistance in human malignancies that express these oncogenes.

Absence of c‐KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer

“…For example, relations between overexpression of EGFR and ERB-B2 and resistance to cisplatin and paclitaxel have been suggested based on in vitro experiments. [35][36][37][38][39] Clinically, amplification and overexpression of ERB-B2 or EGFR have been correlated with an unfavorable outcome in patients with metastatic breast, ovarian, and esophageal carcinoma. 40 -45 Conversely, inhibitors of EGFR and ERB-B2 enhance the antitumor activity of cisplatin in patients expressing these receptor tyrosine kinases, rendering cisplatin- refractory GCTs a target for a comprehensive analysis of these receptors.…”

EGF mutant receptor vIII as a molecular target in cancer therapy.

“…Differential expression of β-tubulin isotypes has been proposed to modulate paclitaxel resistance, and EGFRvIII-expressing cells demonstrated increases in class IV β-tubulin mRNA; inhibition of EGFRvIII kinase activity was also found to decrease expression of class IV of β-tubulin by 50% and to partially reverse resistance to paclitaxel (Montgomery et al 2000). Recently, an interleukin (IL)3-dependent murine hematopoietic cell line (32D cells) transfected with EGFRvIII was reported to abrogate the IL3-dependent pathway in the absence of ligands (Tang et al 2000).…”

“…Cell lines transfected with EGFRvIII are more resistant to paclitaxel-mediated cytotoxicity, and tubulin polymerization induced by paclitaxel is suppressed as compared with that in cells expressing EGFRwt (Montgomery et al 2000). Differential expression of β-tubulin isotypes has been proposed to modulate paclitaxel resistance, and EGFRvIII-expressing cells demonstrated increases in class IV β-tubulin mRNA; inhibition of EGFRvIII kinase activity was also found to decrease expression of class IV of β-tubulin by 50% and to partially reverse resistance to paclitaxel (Montgomery et al 2000).…”

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

“…Although EGFRvIII is unable to bind ligand, it is constitutively phosphorylated and able to activate downstream signalling pathways (Pedersen et al, 2001). EGFRvIII expression is thought to confer resistance to cisplatin and paclitaxel (Nagane et al, 1998;Montgomery et al, 2000). The two studies investigating EGFRvIII expression in ovarian cancer show conflicting results Lassus et al, 2006).…”