There are two main classes of altered molecules that drive cancer – transcriptional regulators and components of kinase-mediated signalling cascades. Most targeted therapeutics act by inhibiting the latter. Use of such drugs has resulted in some spectacular successes in treating previously intractable tumour types, but has generally been plagued by the rapid emergence of resistance.

Comparison of the fundamental roles and architecture of signalling cascades and transcriptional networks helps us to understand the factors that facilitate resistance, and to propose alternative molecular targets for cancer therapy that may be less prone to its emergence. Kinase-driven signalling pathways depend upon a linear architecture, coupled with the convergence of multiple signals on a small number of such pathways. This contrasts with the large number of target genes of transcription factors – typically 100’s to 1000’s – and the extensively interconnected networks within which transcriptional regulators function. Furthermore, transcriptional regulators determine many properties of a particular cancer type; that is, they specify and enforce fundamental gene expression programs that define each cancer.

For these reasons, we propose that it is much less likely that inhibition of an oncogenic transcriptional regulator will be overcome by bypass or secondary mutation mechanisms than is the case for signalling molecules. Moreover, because most transcription factors do not have small-molecule interactors (ligands, substrates etc), they may be less prone to point-mutational resistance to inhibitors.

We are aware however that targeting transcription factors is also much more difficult. Nevertheless there are a number of promising strategies for doing so, as well as a few examples where targeting transcription factors has resulted in effective and enduring suppression of cancer.