Finding cancer's weakest link

Abstract

The biological programs of vertebrates exhibit a remarkable degree of functional degeneracy, adaptive compensation and robustness, to preserve homeostasis and generate reproducible phenotypic outputs irrespective of variations in signal strength, noise and quality. Cancers are difficult to treat not only because they are so mechanistically diverse but also because they adapt or evolve in response to any pharmacological elective pressure we impose upon them. Hence, an ideal cancer drug target would exert a function both necessary for cancer cell survival and functionally non-redundant, rendering it impossible for tumor cells to compensate for, or evolve independence from, the inhibitory effect of any drug aimed at that target. In this review, we discuss the unique, non-degenerate and highly pleiotropic role played by Myc in coordinating, engaging and maintaining the diverse intracellular and extracellular programs required for cell proliferation in vivo. These properties make Myc a compelling candidate cancer drug target, at least in principle: an assertion recently reinforced by new in vivo genetic data.

Figure 1. Schematic model of how the need for robustness in biological systems is reconciled with the need for binary switchability

The consolidated outputs from robust, self-correcting and functionally degenerate information-gathering and information-processing “clouds” (e.g. receptor tyrosine kinases, intracellular kinases, disparate coordinated programs mediating somatic cell replication and propagation) are hypothesized to funnel down into functionally non-degenerate, go/no go switches such Ras, Myc and the activating E2F (E2F1, 2 & 3a) proteins. The obligate and functionally non-degenerate properties of Myc, Ras and E2F make them a unique class of therapeutic drug target, whose inhibition cannot easily be circumvented by compensatory or evolutionary mechanisms. However, the very essentialness of these targets raises the specter of severe side effects. In this regard, Myc has the advantage that, since its sole biological role appears to be in cell proliferation, the only side effects of Myc inhibition are likely to affect regenerating tissues.