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Published on: September 8, 2017
Human mutations that confer paclitaxel resistance
Shanghua Yin1, Rajat Bhattacharya, Fernando Cabral
1Department of Integrative Biology and Pharmacology, University of Texas Medical School, PO Box 20708, Houston, TX 77225, USA.
Abstract:
The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether beta1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in beta1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in beta1-tubulin may require higher drug concentrations for effective therapy.
Insights
Tubulin mutations can cause resistance to paclitaxel, a key chemotherapy drug. Some patients with beta1-tubulin polymorphisms may need higher drug doses for effective cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clinical drug resistance in cancer therapy is a significant challenge.
- Tubulin mutations are a suspected cause of resistance to microtubule-targeting drugs.
- Beta1-tubulin is a critical component of microtubules and a target for chemotherapy.
Purpose of the Study:
- To investigate whether specific beta1-tubulin mutations and polymorphisms found in cancer patients confer resistance to paclitaxel.
- To elucidate the mechanism by which beta1-tubulin mutations affect drug sensitivity and microtubule function.
Main Methods:
- Utilized transfection to introduce specific beta1-tubulin mutations into cancer cells.
- Selected cells in paclitaxel to identify resistant clones.
- Assessed paclitaxel resistance by measuring cell survival and transgene expression.
- Analyzed the impact of mutations on microtubule assembly, mitotic progression, and sensitivity to other microtubule-disruptive agents.
Main Results:
- Three of four tested beta1-tubulin mutations (A185T, A248V, R306C) conferred significant paclitaxel resistance.
- Paclitaxel resistance was directly correlated with the expression level of mutant beta1-tubulin.
- Mutations disrupted microtubule assembly, impaired mitosis, and increased sensitivity to other microtubule-disruptive drugs.
- The G437S mutation did not confer paclitaxel resistance.
Conclusions:
- Human tumor cells can acquire spontaneous beta1-tubulin mutations that lead to paclitaxel resistance.
- Beta1-tubulin mutations likely confer resistance by altering microtubule stability, counteracting paclitaxel's mechanism of action.
- Patients with certain beta1-tubulin polymorphisms may require adjusted paclitaxel dosing for optimal therapeutic outcomes.
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