Targeted molecular strategies for cancer therapy based on the blockage of oncogenic pathways in human tumor cells

Constitutive activation of the extracellular signal-regulated kinase (ERK) and/or phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathways is associated with neoplastic transformation of a variety of human tumor cells. Treatment of such tumor cells with agents that specifically inhibit the activity of mitogen-activated protein kinase/ERK kinase (MEK) or PI3K completely suppresses their proliferation. However, treatment of cells with these inhibitors leads to only a modest increase in apoptotic cell death. Efficient induction of apoptosis is essential for the development of effective cancer chemotherapy. Therefore, we have examined whether specific blockade of these two signaling pathways affects the efficacy of the induction of apoptosis by various anti-cancer agents in tumor cells. We found that MEK inhibitors markedly enhance the efficacy of histone deacetylase inhibitors to induce the generation of reactive oxygen species and apoptosis. This effect was only observed in tumor cells in which the ERK pathway was constitutively activated. Furthermore, we found that PI3K inhibitors selectively and markedly enhanced the efficacy of the induction of apoptosis by doxorubicin. This latter effect was only detected in tumor cells in which the PI3K/Akt pathway was constitutively activated and in which the p53 pathway was functional. These combination treatments provide an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway or PI3K/Akt pathway is constitutively activated. This review gives an overview of the development of new targeted molecular strategies for cancer therapy based on the suppression of the activity of oncogenic pathways involved in the proliferation or survival of tumor cells.