Modulation of cell sensitivity to antitumor agents by targeting survival pathways

The advent of drugs targeting tumor-associated prosurvival alterations of cancer cells has changed the interest of antitumor drug development from cytotoxic drugs to target-specific agents. Although single-agent therapy with molecularly targeted agents has shown limited success in tumor growth control, a promising strategy is represented by the development of rational combinations of target-specific agents and conventional antitumor drugs. Activation of survival/antiapoptotic pathways is a common feature of cancer cells that converge in the development of cellular resistance to cytotoxic agents. The survival pathways implicated in cellular response to drug treatment are primarily PI3K/Akt and Ras/MAPK, which also mediate the signalling activated by growth factors and play a role in the regulation of critical processes including cell proliferation, metabolism, apoptosis and angiogenesis. Inhibitors of PI3K, Akt and mTOR have been shown to sensitize selected tumor cells to cytotoxic drugs through multiple downstream effects. Moreover, the MAPK pathway, also implicated in the regulation of gene expression in response to stress stimuli, can interfere with the chemotherapy-induced proapoptotic signals. Targeting Hsp90, which acts as a molecular chaperone for survival factors including Akt, may have the potential advantage to simultaneously block multiple oncogenic pathways. Overall, the available evidence supports the interest of rationally designed approaches to enhance the efficacy of conventional antitumor treatments through the inhibition of survival pathways and the notion that the concomitant targeting of multiple pathways may be a successful strategy to deal with tumor heterogeneity and to overcome drug resistance of tumor cells.