Paclitaxel Resistance in Non–Small-Cell Lung Cancer Associated With Beta-Tubulin Gene Mutations

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Abstract
PURPOSE: The mechanisms that cause chemoresistance in non–small-cell lung cancer (NSCLC) patients have yet to be clearly elucidated. Paclitaxel is a tubulin-disrupting agent that binds preferentially to beta-tubulin. Tubulins are guanosine triphosphate (GTP)–binding proteins. Beta-tubulin is a GTPase, whereas alpha-tubulin has no enzyme activity. We reasoned that polymerase chain reaction (PCR) and DNA sequencing of the beta-tubulin gene could reveal more information regarding the connection between beta-tubulin mutations and primary paclitaxel resistance. PATIENTS AND METHODS: Constitutional genomic DNA and paired tumor DNA were isolated from 49 biopsies from 43 Spanish and six American stage IIIB and IV NSCLC patients who had been treated with a 3-hour, 210 mg/m2 paclitaxel infusion and a 24-hour, 200 mg/m2 infusion, respectively. Oligonucleotides specific to beta-tubulin were designed for PCR amplification and sequencing of GTP- and paclitaxel-binding beta-tubulin domains. RESULTS: Of 49 patients with NSCLC, 16 (33%; 95% confidence interval [CI], 20.7% to 45.3%) had beta-tubulin mutations in exons 1 (one patient) or 4 (15 patients). None of the patients with beta-tubulin mutations had an objective response, whereas 13 of 33 (39.4%; 95% CI, 22.8% to 56%; P = 0.01) patients without beta-tubulin mutations had complete or partial responses. Median survival was 3 months for the 16 patients with beta-tubulin mutations and 10 months for the 33 patients without beta-tubulin mutations (P = .0001). CONCLUSION: We have identified beta-tubulin gene mutations as a strong predictor of response to the antitubulin drug paclitaxel; these mutations may represent a novel mechanism of resistance and should be examined prospectively in future trials of taxane-based therapy in NSCLC.

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