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mechanism of her2+ breast cancer resistance to taxol discovered
This is done in a petri dish on cell lines, not in whole human beings and is not to say that all her2+ breast cancers are resistant. Neither does this prove that this is the only path to resistance. It does give scientists a better idea of how to predict and perhaps prevent the resistance before it happens ie, find anti-survivin drugs and combine them with taxol/taxanes (docetaxol ,etc). Best to try to keep one step ahead of the cancer!
Clin Cancer Res. 2009 Feb 15;15(4):1326-34.
Mitotic Deregulation by Survivin in ErbB2-Overexpressing Breast Cancer Cells Contributes to Taxol Resistance.
Lu J, Tan M, Huang WC, Li P, Guo H, Tseng LM, Su XH, Yang WT, Treekitkarnmongkol W, Andreeff M, Symmans F, Yu D.
Authors' Affiliations: Departments of Molecular and Cellular Oncology, Stem Cell Transplantation, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
PURPOSE: Taxol resistance remains a major obstacle to improve the benefit of breast cancer patients. Here, we studied whether overexpression of ErbB2 may lead to mitotic deregulation in breast cancer cells via up-regulation of survivin that confers Taxol resistance. EXPERIMENTAL DESIGN: ErbB2-overexpressing and ErbB2-low-expressing breast cancer cell lines were used to compare their mitotic exit rate, survivin expression level, and apoptosis level in response to Taxol. Survivin was then down-regulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2-overexpressing breast cancer cells. At last, specific PI3K/Akt and Src inhibitors were used to investigate the involvement of these two pathways in ErbB2-mediated survivin up-regulation and Taxol resistance. RESULTS: We found that ErbB2-overexpressing cells expressed higher levels of survivin in multiple breast cancer cell lines and patient samples. ErbB2-overexpressing cells exited M phase faster than ErbB2-low-expressing cells, which correlated with the increased resistance to Taxol-induced apoptosis. Down-regulation of survivin by antisense oligonucleotide delayed mitotic exit of ErbB2-overexpressing cells and also sensitized ErbB2-overexpressing cells to Taxol-induced apoptosis. Moreover, ErbB2 up-regulated survivin at translational level and PI3K/Akt and Src activation are involved. In addition, combination treatment of Taxol with PI3K/Akt and Src inhibitor led to increased apoptosis in ErbB2-overexpressing breast cancer cells than single treatment. CONCLUSIONS: Survivin up-regulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.
PMID: 19228734
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