Abstract
Patupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III beta-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3 expression (OVCAR-3). The obtained cell lines were named EPO3 and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drug-resistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3 in TAX50, but not EPO3, cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were sequenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I beta-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxel-platin chemotherapy.
Highlights
Microtubule-targeting agents are widely used for cancer treatment
The levels of TUBB3 increased 5-fold in cells grown www.aacrjournals.org in the presence of 50 nmol/L paclitaxel (TAX50), but this was not detected in A2780 cells selected with patupilone, hereafter referred to as EPO3x cells, where x corresponds to the patupilone dose used for the selection
This cell line was chosen for its native drug resistance and high expression levels of TUBB3
Summary
Microtubule-targeting agents are widely used for cancer treatment. Microtubule-targeting agents are classically divided into drugs acting as inhibitors and those as enhancers of tubulin polymerization, it is likely that at the low drug concentrations obtainable in patients, both groups act through inhibition of microtubule dynamics [1]. The taxanes paclitaxel and docetaxel are widely used in treatments of solid tumors They are two natural compounds that enhance tubulin polymerization and share the same framework (10-deacetylbaccatin III, obtained from Taxus spp. throughout the world) and are approved for clinical use in ovary, lung, breast, head and neck, gastric, and prostate cancers. The development of novel taxanes has been mainly guided by selecting lead compounds for the activity against P-glycoprotein (P-gp), the gene product of the ABCB1 (MDR) gene This has resulted in the clinical development of a series of taxanes able to potently inhibit the P-gp function, but their response rates in phase II clinical studies were disappointingly lower than expected, showing that this resistance mechanism, which is observable in cultured cell lines [3], does not operate in patients with solid tumors [2]. The results show that the mechanisms underlying patupilone resistance are significantly different from those responsible for taxane resistance, thereby providing a molecular basis for identifying the subset of patients who are potentially responsive to this novel therapy and the background to a sequential combination of the two drugs in distinct clinical subsets
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