biomarker predicting sensitivity (or resistance) to taxanes

[Lani]

Needs to be tested in large numbers of patients to confirm, but promising.

One of the cell lines used in the study was SKBR3, WHICH IS her2+ER-PR-

ABSTRACT: Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of ?-tubulins [International Journal of Cancer]
The antineoplastic effect of paclitaxel is mainly related to its ability to bind the ? subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. The relevance of the Class I ?-tubulin characteristics have also been confirmed in the clinical setting where mutations of paclitaxel-binding site of ?-tubulin Class I have been related to paclitaxel resistance in non small cell lung and ovarian cancers. In the present study, we verified the hypothesis of a relationship between molecular alterations of ?-tubulin Class I and paclitaxel sensitivity in a panel of breast cell lines with different drug IC50. The Class I ?-tubulin gene cDNA has been sequenced detecting heterozygous missense mutations (exon 1 and 4) only in MCF-7 and SK-BR-3 lines. Furthermore, the expression (at both mRNA and protein level) of the different isotypes have been analyzed demonstrating an association between low cell sensitivity to paclitaxel and Class III ?-tubulin expression increasing. Antisense oligonucleotide (ODN) experiments confirmed that the inhibition of Class III ?-tubulin could at least partially increase paclitaxel-chemosensitivity. The hypothesis of a relationship between ?-tubulin tumor expression and paclitaxel clinical response has been finally verified in a series of 92 advanced breast cancer patients treated with a first line paclitaxel-based chemotherapy. Thirty-five percent (95% CI: 45-31) of patients with high Class III ?-tubulin expression showed a disease progression vs. only 7% of patients with low expression (35% vs. 7%, p < 0.002). Our study suggests that Class III ?-tubulin tumor expression could be considered a predictive biomarker of paclitaxel-clinical resistance for breast cancer patients.