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New macromolecules lay the foundations for new cancer therapeutics 1

Researchers from the MRC WIMM working in collaboration with scientists from AstraZeneca have designed new macromolecules which could potentially be developed as future cancer therapeutics with a greater targeted approach.

For some time, research and development of new cancer medicines have focused on discovering and targeting the genetic drivers and resistance mechanisms of cancer. By identifying the mechanisms through which tumour cells grow and divide (proliferate), we can develop drugs that target these molecules

“By identifying key proteins that are specific to cancer cells, we can then develop tailor-made drugs that impair the function of these specific proteins,” said Professor Terry Rabbitts from the MRC WIMM and MRC MHU, who co-led the study.

A good candidate for such a key protein to target is KRAS, from a protein family that participates in pathway relaying signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and proliferate: functions which are abnormal in cancer cells.

Previous work has found that the KRAS protein is altered in a quarter of human cancers: while the normal protein switches between active and inactive forms, mutant KRAS is in a permanently active state, telling the affected cell to keep dividing without dying. So this is a good protein to try and block to develop therapies that only target cancer cells.

 “The problem is that it is very challenging to specifically target only one member of this protein family, because all the proteins in this family are so similar to each other,” said Dr Nicolas Bery, the first author on the study. “There are small molecules that can block KRAS selectively, but they only work for one particular KRAS mutation that makes up just 12% of cancer-causing KRAS mutations.”

“While earlier work from our lab identified compounds that can block all the members of the RAS family, we needed to find ways to block just the KRAS protein.”

So working with colleagues at AstraZeneca’s BioPharmaceuticals R&D, the Rabbitts lab has been developing a new approach focussed on using fragments of antibodies that normally track invasive proteins or viruses circulating inside cells.  By looking for a new antibody-like fragment that can interfere with KRAS inside cells, the research team identified two Designed Ankyrin Repeat Proteins (DARPins, pictured in green) that attach only to KRAS (pictured, in tan) and do not bind the other RAS family members. When the DARPins were artificially expressed in human cancer cells, they only affected mutant KRAS proteins, but not its family members, NRAS or HRAS, even when these were mutated.

“There have been debates in the RAS community for a long time over the relative importance of each RAS isoform, with KRAS generally regarded as the most relevant target for cancer therapy. These DARPins identify a key binding site which enables exquisite KRAS specificity and provide tools to further investigate downstream biology.”, added Ralph Minter, Senior Director, Antibody Discovery & Protein Engineering, BioPharmaceuticals R&D, AstraZeneca.

The team also found that their novel DARPins were blocking the mutant KRAS protein’s function in two different ways, and they attached themselves to the protein at a different place from previous blockers.

“We now need to solve the problem of protein delivery to cells to actually use these molecules as drugs in patients,” said Professor Rabbitts.

The paper is published in Nature Communications.