By Moitreyee Chatterjee-Kishore, Ph.D., MBA, Head of Oncology Development, Astellas Pharma Inc.
Researchers have long sought new ways to disable or inhibit cancer-driving proteins. Many transformative therapies have been built on this paradigm.
Yet, for many of these proteins, such as KRAS, structural complexity or a lack of clear binding sites has made them difficult to target using conventional approaches. Even when inhibition is possible, tumors can adapt by developing secondary mutations or continue to cause harm due to their remaining activity.
And that is exactly why Astellas has spent more than a decade pioneering targeted protein degradation – an emerging paradigm shift that aims to remove the disease-causing protein altogether. With a lead program now in late-stage clinical development for KRAS-driven cancers, we believe it’s a defining moment for targeted protein degraders seeking to address disease at its biological root.
The challenge posed by KRAS-driven cancers
Approximately 11% of all cancers carry KRAS mutations. Often aggressive, biologically adaptable and the majority still lack approved mutation-specific therapies.
The KRAS protein lacks a “deep pocket” for traditional stable drug binding, occurs in several mutation-specific forms that alter these proteins in distinct ways, and they can adapt, resisting traditional therapeutic approaches that suppress pathways critical for tumor growth.
For patients living with KRAS-driven cancers, the implications are significant.
The ability to directly eliminate a disease-causing protein through degradation could redefine treatment: moving from managing downstream effects to addressing a central driver of disease biology.
Targeted protein degradation – a paradigm shift for addressing KRAS-driven cancers
Targeted protein degradation offers a new way of thinking about this challenge. Rather than relying on the “deep pocket” to bind and inhibit activity, protein degraders eliminate the protein altogether.
Unlike inhibition which typically requires a sustained target engagement to maintain effect, targeted protein degraders use the body’s natural protein quality-control system – tagging unwanted disease-causing proteins for destruction.
By reducing levels of disease-driving proteins within cancer cells, targeted protein degraders may also help address resistance mechanisms linked to protein overexpression and more directly influence tumor biology.
Accelerating momentum for a new era of targeted protein degradation
At Astellas, our disease-led, biology-first innovation approach has guided sustained investment in targeted protein degradation capabilities alongside KRAS inhibitor research. By bringing these efforts together, we discovered setidegrasib, the first protein degrader specifically targeting the KRAS G12D mutation to enter the clinic.
KRAS G12D is one of the most prevalent KRAS mutations, found in ~40% of pancreatic ductal adenocarcinomas and ~5% of non-squamous non-small cell lung cancers, with no approved mutation-specific targeted treatment options.
Setidegrasib is now being evaluated in two Phase 3 studies, in first line pancreatic ductal adenocarcinoma and in second line non‑small cell lung cancer – building on early clinical evidence published in The New England Journal of Medicine that demonstrated clear antitumor activity and a manageable safety profile.
Expanding the therapeutic playbook
Importantly, at Astellas, we don’t view targeted protein degradation as a single‑asset story. It represents a breakthrough modality with the potential to reshape multiple areas of medicine.
With initial efforts focusing on specific cancer-driving mutations, programs such as our pan-KRAS protein degrader that recently entered the clinic are designed to target multiple KRAS mutations, simultaneously.
What’s next for targeted protein degraders – from individual programs to a scalable platform
Critically, these advances are not limited to KRAS targets alone. Protein degraders are also relatively small molecules that can reach targets with biological barriers that were previously considered “undruggable.”
As a result, targeted protein degradation is opening the door to innovation beyond oncology, including other disease areas where targeted elimination of specific proteins could unlock new therapeutic possibilities and deliver meaningful clinical impact – bringing the field one step closer to finding the answers patients with limited options desperately need.
The editorial staff had no role in this post's creation.