Expression of Class III β-Tubulin Is Predictive of Patient Outcome in Patients with Non–Small Cell Lung Cancer Receiving Vinorelbine-Based Chemotherapy

Abstract

Purpose: To determine the prevalence and the prognostic value of microtubule component expression in tumors of patients with locally advanced or metastatic non^small cell lung cancer (NSCLC). Experimental Design: Expression of microtubular components was immunohistochemically examined in 93 tumor samples from untreated patients with stage III and IV NSCLC. All patients received vinorelbine-based chemotherapy. Response to chemotherapy, progressionfree survival, and overall survival were correlated with the expression of microtubule proteins. Results: The response rate was 27.3% (21 partial responses among 77 valuable patients). Although expression of microtubule components was not associated with the response rate, high class III h-tubulin expression was correlated with resistance to vinorelbine, defined as disease progression under treatment. Patients whose tumors expressed high levels of class III h-tubulin isotype had shorter progression-free survival and overall survival (P = 0.002 and 0.001, respectively). High D2 a-tubulin expression was associated with a shorter overall survival (P = 0.018). Tubulin II levels were not found to be correlated with patient outcome. A multivariate analysis, taking into account sex, age, histology, stage, weight loss, and class II h-tubulin, class III h-tubulin, and D2 a-tubulin levels, confirmed that class III h-tubulin expression was independently correlated with progression-free survival (P = 0.04) and overall survival (P = 0.012). Conclusions:These findings suggest that a high level of expression of class III h-tubulin in tumor cells is associated with resistance to vinorelbine and a poor prognosis in patients with NSCLC receiving vinorelbine-based chemotherapy.

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

“…This may be a great advantage when class III b-tubulin is overexpressed and the microtubule dynamic is amplified. However, vinorelbine, which is also a microtubule-destabilising agent but binds to the Vinca alkaloid binding site, has its efficacy reduced by the overexpression of class III b-tubulin in vitro in breast carcinoma cells (as shown in this study) and in small lung cancer cells (Gan et al, 2007) and in vivo (Seve et al, 2005). Therefore, class III b-tubulin resistance might be binding-site related and agents binding to the colchicine-binding site might avoid this resistance.…”

“…In summary, this study shows that microtubule disrupting agents binding to the colchicine-binding site circumvent class III b-tubulin resistance, whereas agents binding to the taxol-or the Vinca-binding sites have their efficacies altered by changes in class III b-tubulin expression. Class III b-tubulin is associated with drug resistance and poor prognosis in patients (Hasegawa et al, 2003;Mozzetti et al, 2005;Seve et al, 2005;Urano et al, 2006;Tommasi et al, 2007) and it is a predictive factor of event-free and overall survival (Seve and Dumontet, 2008). Moreover, class III b-tubulin is involved in the sensitivity of both taxanes and Vinca alkaloids, but it also has a role in chemosensitivity of DNA-damaging agents (Gan et al, 2007).…”

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

“…Microtubules consisting of the βIII-tubulin isotype have altered assembly properties, requiring a larger critical mass of tubulin for assembly, and polymerizing at a slower rate than other isotypes (16). In vitro, the overexpression of βIII tubulin results in increased resistance to taxane and vinorelbine (17,18). Elevated expression of βIII tubulin has also been correlated with clinical resistance to taxanes in a number of human cancers (19).…”

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

“…TUBB3 has assumed an important role as a clinical marker of drug resistance in ovary (16), lung (17), stomach (18), pancreas (19), and breast (20) cancer patients. Due to the relevance clinically proven as a factor of drug resistance, here we report the results of a proteomic analysis of TUBB3 aimed to better characterize the protein function and possibly develop novel approaches to prevent or circumvent TUBB3-mediated drug resistance.…”