Vertical pathway targeting in cancer therapy.

Malignant cells arise from particular mutations in genes controlling cell proliferation, invasion, and survival. Older antineoplastic drugs were designed to target vital cellular processes, such as DNA maintenance and repair and cell division. As a result, these drugs can affect all proliferating cells and are associated with unavoidable toxicities. Recent discoveries in cancer research have identified "driver" mutations in some types of cancer, and efforts have been undertaken to develop drugs targeting these oncogenes. In most cases, due to escape mechanisms and adaptive responses, single oncogene targeting is insufficient to induce prolonged responses in solid tumors. Drug combinations are therefore used to enhance the growth inhibitory and cytotoxic effects of the targeted therapies. Depending on the position of additional targets within the signaling network, drug combinations may target either different signaling pathways (parallel targeting) or the same pathway at several fragile nodes (vertical targeting). In this review, we discuss strategies of multitarget inhibition with a focus on vertical signaling pathway targeting.