Oncogene-Induced Vulnerabilities
Oncogenic mutations do more than simply drive unscheduled proliferation – they requisition entire suites of cellular programmes that impinge upon almost every aspect of cellular function. Our overarching hypothesis is that, as tumours evolve, some of these oncogene-induced alterations will be selectively required by cancer cells to maintain viability. We have used a synthetic lethal approach to identify kinases required by cells that overexpress c-Myc. Intriguingly, our screen identified a number of metabolic regulators, suggesting that Myc-driven tumours may be particularly sensitive to disruption of metabolic checkpoints. Indeed we have recently demonstrated that cells overexpressing Myc are critically dependent upon AMPK and the closely related kinase ARK5 in order to maintain ATP homeostasis and thereby viability (Liu, Ulbrich et al., Nature 2012). This exciting result suggests that pharmacological suppression of Ark5/AMPK may have broad therapeutic potential against a spectrum of human cancers. Furthermore, we have developed a number of conditional transgenic mouse models of cancer that enable us to humanely track the entire course of early disease through tumour initiation and progression in situ. The use of inducible RNAi transgenic technology will now enable us to accurately model therapeutic intervention against existing tumours in mice with a higher degree of genetic “on-target” certainty than is typically afforded by nascent pharmacological agents. The use of these models to compliment cell culture based approaches is essential for a complete mechanistic understanding of the many processes involved in cancer as well as for more realistic pre-clinical evaluation of candidate therapies.
Synthetic lethality of Ark5 suppression in Myc overexpressing cells. We used the hydroxytamoxifen- inducible Myc-Estrogen Receptor ligand binding domain fusion protein (MycERT2) to acutely deregulate Myc in U2OS cells proficient for or depleted of Ark5. Failure to maintain ATP homeostasis in the absence of Ark5 leads to a highly selective, synchronous and catastrophic collapse of the Myc over expressing population.