Increasing the anticancer efficacy of docetaxel by ERK inhibitors

Prostate carcinoma is the most common malignancy and second leading cause of cancer death in men in the United States. Approximately 180,400 new cases of prostate cancer are diagnosed each year. Prostate cancers generally respond to androgen ablation therapy. However, such treatment is not curative, and the disease progresses to an androgen-independent stage. Effective treatment for advanced hormone-refractory cancers remains a significant challenge (click here for an overview of pharmaceutical approaches to prostate cancer).

Apoptosis is induced in malignant cells by a wide range of anticancer drugs and novel approaches to the stimulation of apoptosis continue to emerge. The induction of endogenous inhibitors of apoptosis such as Bcl-2 or IAPs by chemo- or radio-therapy contributes to the resistance of tumor to treatment. Thus one recent strategy has been to inhibit endogenous inhibitors of apoptosis such as members of the Bcl-2 and “Inhibitor of Apoptosis Protein" (IAP) families.

Microtubule-disrupting agents represent a key class of chemotherapeutics stimulating cells to undergo cell-cycle arrest and cell death. Docetaxel (Taxotere) interacts with polymerized tubulin and inhibits its depolymerization. This new member of the taxane family is in development for the treatment of prostate cancer. The combination of docetaxel with treatments that inhibit survival signals may improve the efficacy of chemotherapeutic strategies by limiting drug resistance and since the ERK pathway plays an important role in cell survival the use of ERK inhibitors along side docetaxel may be particularly beneficial.

ERK is activated by MEK and inhibitors of this enzyme such as U0126 and PD98059 can block activation of ERK. In a recent study Zelivianski et al report that a combination of PD98059 plus sub-clinical concentrations of docetaxel suppresses the proliferation of prostate cancer cell lines and increases their apoptotic index to a greater extent than either molecule alone. This effect was most evident in highly tumorigenic and androgen insensitive cells, characteristics that were mirrored by high levels of ERK activity. At a molecular level, the presence of PD98059 caused a dramatic phosphorylation of Bcl-2 that is known to lead to a loss of antiapoptotic activity. In addition PD98059 also reduced the expression of a second anti-apoptotic molecule, Bcl-XL and increased the expression of Bax, homodimers of which are apoptotic.

In general no single cytotoxic agent produces an objective response rate greater that 30% in prostate cancer patients and weekly exposure of lower doses is more effective than higher doses. Adjunctive use of molecules such as PD98059 is expected to improve the efficacy and lower the minimally active dose of docetaxel and other microtubule stabilizers. Support of this concept appeared in a press release recently described in our intelligence tracker, DailyUpdates. This release reported that the combination of Genasense (oblimersen sodium), a biologic agent that targets Bcl-2, and docetaxel produced a 50% reduction in PSA levels in heavily pre-treated prostate cancer patients. A trial directly comparing docetaxel alone to docetaxel plus Genasense has been initiated and similar studies combining small molecule inhibitors of ERK (such as PD98059), which the present study found to have a similar effect on Bcl-2, and docetaxel are eagerly awaited.