Targeted protein degraders from an oncologist point of view: The Holy Grail of cancer therapy?

In the era of precision medicine, monoclonal antibodies and small molecule inhibitors are the mainstays of the biological therapy in patients with solid tumors. However, resistance to treatment and the "undruggability" of certain key oncogenic proteins emerged as major limitations and jeopardize the clinical benefit of modern therapeutic approaches. Targeted protein degraders are novel molecules entering the early phase of clinical development that exploit the intracellular ubiquitine-proteasome system to promote a specific degradation of target proteins. Since the peculiar mechanism of action, targeted protein degraders have the potential to limit and overcome resistance to treatment and to allow a full actionability of certain cancer drivers that are actually elusive targets. Here, we discuss the state-of-the-art and the open issues in the development of these emerging biological agents from a clinical perspective and with a focus on solid tumors.