Targeting multiple kinase pathways: a change in paradigm

Abstract

Anticancer drugs that target protein kinases include small molecule inhibitors and monoclonal antibodies. Feedback loops and cross talk between signaling pathways impact significantly on the efficacy of cancer therapeutics, and resistance to targeted agents is a major barrier to effective treatments. Increasingly, therapies are being designed to target multiple kinase pathways. This can be achieved using a single agent that inhibits multiple signaling pathways or a combination of highly selective agents. In this review we discuss the principles of specifically targeting multiple kinase pathways with particular reference to angiogenic signaling pathways.

Figure 1a. VEGF signalling and potential therapeutic targets

The binding of VEGF to its receptor initiates activation of both the PI3K-Akt and RAF-MEK-ERK pathways (1). Each pathway has its own distinct downstream effects. However, they also converge on at least two important downstream targets, mTORC1 (2) and BAD (3), which plays a key role in apoptosis. Furthermore, Ras binds directly to PI3K and each influences activation of the other pathway(4). mTORC1 inhibition leads to activation of both PI3K and ERK signalling by abrogating feedback inhibition (5). Potential points of therapeutic inhibition are highlighted. Components in the signalling pathway that are mutated in cancers are shown in pink.

Figure 1b. Combination therapies including mTOR Inhibitors

Combining mTOR-Is with VEGF antagonists such as bevacizumab may result in additive or synergistic efficacy. Alternatively, preclinical evidence suggests that combining mTOR-Is with MEK-Is and/or PI3K-Is may improve clinical efficacy by abrogating downstream effects induced by mTORC-I induced activation of the RAF-MEK-ERK and PI3K pathways.

Figure 1c. Combinations of EGFR-Is and PI3K-Is may improve clinical efficacy

Reactivation of PI3K signalling is a common mechanism of resistance to therapies targeting the EGFR. Combining these agents with PI3K-Is may be one way to overcome this resistance mechanism.