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


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/m(2) paclitaxel infusion and a 24-hour, 200 mg/m(2) 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).


CONCLUSIONS
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.
Monzó
M
M
Department of Pathology and the Laboratory of Molecular Biology of Cancer, Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Rosell
R
R
Sánchez
J J
JJ
Lee
J S
JS
O'Brate
A
A
González-Larriba
J L
JL
Alberola
V
V
Lorenzo
J C
JC
Núñez
L
L
Ro
J Y
JY
Martín
C
C
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017239:Paclitaxel / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D015996:Survival Rate; D014404:Tubulin / Q000235:genetics*
D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D017239:Paclitaxel