ABCB4 p.Ala364Thr
| Predicted by SNAP2: | C: N (61%), D: D (80%), E: D (80%), F: D (75%), G: N (78%), H: D (71%), I: D (59%), K: D (75%), L: D (66%), M: D (63%), N: D (66%), P: D (80%), Q: D (71%), R: D (75%), S: N (57%), T: N (53%), V: D (66%), W: D (71%), Y: D (75%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Paclitaxel-resistant cells have a mutation in the ... Mol Cancer Ther. 2006 Feb;5(2):270-8. Hari M, Loganzo F, Annable T, Tan X, Musto S, Morilla DB, Nettles JH, Snyder JP, Greenberger LM
Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules.
Mol Cancer Ther. 2006 Feb;5(2):270-8., [PMID:16505100]
Abstract [show]
Resistance to paclitaxel-based therapy is frequently encountered in the clinic. The mechanisms of intrinsic or acquired paclitaxel resistance are not well understood. We sought to characterize the resistance mechanisms that develop upon chronic exposure of a cancer cell line to paclitaxel in the presence of the P-glycoprotein reversal agent, CL-347099. The epidermoid tumor line KB-3-1 was exposed to increasing concentrations of paclitaxel and 5 micromol/L CL-347099 for up to 1 year. Cells grown in 15 nmol/L paclitaxel plus CL-347099 (KB-15-PTX/099) developed 18-fold resistance to paclitaxel and were dependent upon paclitaxel for maximal growth. They grew well and retained resistance to paclitaxel when grown in athymic mice. Cross-resistance (3- to 5-fold) was observed in tissue culture to docetaxel, the novel taxane MAC-321, and epothilone B. Collateral sensitivity (approximately 3-fold) was observed to the depolymerizing agents vinblastine, dolastatin-10, and HTI-286. KB-15-PTX/099-resistant cells did not overexpress P-glycoprotein nor did they have an alteration of [14C]paclitaxel accumulation compared with parental cells. However, a novel point mutation (T to A) resulting in Asp26 to glutamate substitution in class I (M40) beta-tubulin was found. Based on an electron crystallography structure of Zn-stabilized tubulin sheets, the phenyl ring of C-3' NHCO-C6H5 of paclitaxel makes contact with Asp26 of beta-tubulin, suggesting a ligand-induced mutation. Optimized model complexes of paclitaxel, docetaxel, and MAC-321 in beta-tubulin show a novel hydrogen bonding pattern for the glutamate mutant and rationalize the observed resistance profiles. However, a mutation in the paclitaxel binding pocket does not explain the phenotype completely. KB-15-PTX/099 cells have impaired microtubule stability as determined by a reduced percentage of tubulin in microtubules and reflected by less acetylated tubulin. These results suggest that a mutation in tubulin might affect microtubule stability as well as drug binding and contribute to the observed resistance profile.
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No. Sentence Comment
194 This has been observed in 1A9 cells made resistant to paclitaxel that harbor the mutation Phe270 Val or Ala364 Thr, where mutant tubulin mRNA is preferentially expressed.
X
ABCB4 p.Ala364Thr 16505100:194:104
status: NEW