Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations

: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, Tubulin s are guanosine triphosphate (GTP)-binding proteins. Beta-tubulin is a GTPa se, whereas alpha-tubulin has no enzyme activity. We reasoned that polymera se chain reaction (PCR) and DNA sequencing of the beta-tubulin gene could r eveal more information regarding the connection between beta-tubulin mutati ons 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 I V NSCLC patients who had been treated with a 3-hour, 210 mg/m(2) paclitaxel infusion and a 24-hour, 200 mg/m(2) infusion, respectively Oligonucleotide s specific to beta-tubulin were designed for PCR amplification and sequenci ng 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 (1 5 patients). None of the patients with beta-tubulin mutations had an object ive response, whereas 13 of 33 (39.4%; 95% CI, 22.8% to 56%; P = 0.01) pati ents without beta-tubulin mutations had complete or partial responses. Medi an survival was 3 months for the 16 patients with beta-tubulin mutations an d 10 months for the 33 patients without beta-tubulin mutations (P = .0001). Conclusion: We have identified beta-tubulin gene mutations as a strong pred ictor of response to the antitubulin drug paclitaxel;these mutations may re present a novel mechanism of resistance and should be examined prospectivel y in future trials of taxane-based therapy in NSCLC. (C) 1999 by American S ociety of Clinical Oncology.