Finding a Cancer “Off Switch”

What if curing cancer could be as simple as flipping a switch from “on” to “off”? Findings in a study published today in Nature Communications show that our scientists may have gotten one step closer.

Scientists at MedImmune, the global biologics research and development arm of AstraZeneca, as well as AstraZeneca’s IMED Biotech Units—together with researchers at Oxford University—have found that a mutant protein linked to cancer can be neutralized. This advancement raises hope that highly specific small biologics can be developed to “turn off” a cancer-causing mutation — a concept that builds upon groundwork work from the Oxford scientists and demonstrates an approach that had been previously considered unfeasible by many in the scientific community.

Understanding Mutant Ras

Our target is Ras, a protein that resides inside cells and plays a critical a role in cellular proliferation. Guanosine triphosphate (GTP) binds to normal Ras inside the cell, creating an active form—or “on” form—of Ras that allows other proteins to bind to Ras and carry the signal onward. Ras then turns GTP into guanosine diphosphate (GDP), causing Ras to change into an off-position shape to which downstream signaling proteins cannot bind. Eventually, GDP is removed from Ras allowing GTP to bind again, reactivating Ras by changing it back to the active shape.

Mutant Ras causes cells to multiply uncontrollably because it is “locked on”, suggesting this causes cancer cells to reproduce uncontrollably resulting in aggressive disease resistant to most therapies. Because of this, mutant Ras has been a prime target for designing anti-cancer therapies. To target it with a biologic, we needed to get a “large molecule” into the cell.

Collaboration to Challenge Convention

Researchers at MedImmune and IMED took on two approaches to target mutant Ras. First, they had the hypothesis that the active form of mutant Ras is not permanently “locked on” but is changed into the “off” state before being reactivated. If true, it might be possible to permanently capture this inactive form using a biologic tool.

Next, MedImmune scientists created a specific Designed Ankyrin Repeat Proteins (DARPin) – an antibody-like protein yet one-tenth of the size of a full-length antibody, which is very stable inside cells and easily engineered to perform specific functions – to bind to the inactive mutant Ras-GDP and lock it in the off-state and prevent it from being switched on. IMED Biotech scientists added their expertise in protein crystallography, and together the teams confirmed the mechanism of action. 

The next step was to demonstrate that the specific DARPin, K27, inhibits Ras signaling in living cells. Oxford University scientists provided expertise to show that cells that contain mutant Ras, artificially induced to express K27, exhibited inhibition of all known Ras signaling pathways. K27 also stopped cell growth and proliferation, compared with cells not expressing K27, providing the final evidence supporting this potential approach in cancer therapy. 

So, Can We ‘Turn Off’ Cancer?

Not quite. But this work, while preliminary, shows that a biologic tool could be designed to bind to mutant Ras and lock it in the off-state, laying the groundwork for new strategies for designing anti-cancer therapeutics.

We will continue to follow the science and to bring together the relevant expertise, both within and outside of MedImmune. These collaborations are critical to finding scientific solutions, even if it means overturning conventional wisdom along the way.

References:

Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange. Guillard, S. et al. Nature Communications. Published Online First: July 14, 2017. 10.1038/NCOMMS16111: https://www.nature.com/articles/ncomms16111