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Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations
M Monzó1, R Rosell, J J Sánchez
1Department of Pathology and the Laboratory of Molecular Biology of Cancer, Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
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/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).
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.
Insights
Beta-tubulin gene mutations predict poor response to paclitaxel in non-small-cell lung cancer (NSCLC). These mutations represent a novel chemoresistance mechanism and warrant further investigation in NSCLC treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemoresistance in non-small-cell lung cancer (NSCLC) remains a significant clinical challenge.
- Paclitaxel, a tubulin-disrupting agent, efficacy is influenced by beta-tubulin interactions.
- Understanding resistance mechanisms is crucial for optimizing NSCLC therapy.
Purpose of the Study:
- To investigate the association between beta-tubulin gene mutations and primary paclitaxel resistance in NSCLC patients.
- To explore beta-tubulin mutations as a potential mechanism for paclitaxel chemoresistance.
Main Methods:
- Genomic DNA was extracted from 49 NSCLC patient biopsies (43 Spanish, 6 American).
- Polymerase chain reaction (PCR) and DNA sequencing were employed to analyze beta-tubulin gene domains.
- Patients received paclitaxel infusions at standard doses and durations.
Main Results:
- Beta-tubulin mutations were identified in 16 out of 49 (33%) NSCLC patients, primarily in exon 4.
- Patients with beta-tubulin mutations showed no objective response to paclitaxel (0% vs. 39.4% in wild-type).
- Median survival was significantly shorter for patients with mutations (3 months vs. 10 months, P=.0001).
Conclusions:
- Beta-tubulin gene mutations are a strong predictor of poor response to paclitaxel in NSCLC.
- These mutations represent a novel mechanism of primary paclitaxel resistance.
- Prospective evaluation of beta-tubulin mutations in taxane-based therapy trials for NSCLC is recommended.