Paradoxical activation of oncogenic signaling as a cancer treatment strategy.

Cancer cell homeostasis requires a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs to counteract the inherent toxicity of such aberrant signaling.

Indeed, emerging evidence suggests that hyperactivated oncogenic signaling can also be toxic to cancer cells, indicating that cancer cells select optimal levels of oncogenic signaling rather than maximal levels.

I propose here a fundamentally different approach to the treatment of cancer, based on deliberate hyperactivation of oncogenic signaling, combined with perturbation of the activated stress responses to selectively kill cancer cells.

We will use drugs that further activate oncogenic signaling in cancer cells (protein phosphatase 2A (PP2A) inhibitors, GSK3 inhibitors, PKC activators, DUSP inhibitors) and study the associated toxicities using single cell omics technologies. We will then use CRISPR and compound screens to identify the vulnerabilities of such drug-treated cells.

This will identify effective combination therapies using this paradoxical approach.

We have delivered initial proof of concept for this notion by demonstrating that hyper-activation of oncogenic signaling in colon cancer by small molecule inhibition of PP2A, combined with inhibition of the mitotic kinase WEE1 results in dramatic anti-tumor responses in vivo.

Most strikingly, we found that cancer cells develop resistance to this therapy through selective downregulation of oncogenic signaling to evade the stress imposed by hyperactivation of oncogenic signaling.

Consequently, resistance to this hyperactivation therapy was associated with both reduced oncogenic signaling and oncogenic traits in vivo.

Here, we aim to understand and exploit toxicities associated with paradoxical activation of oncogenic signaling using multi-omics technologies, study how cancer cells can develop tumor suppressive drug resistance and address the effects of this type of therapy on pre-malignant lesions.