Approximately 20% of all cancers harbor a mutation in one of the four members of the RAS family of small GTPases, KRAS4A, KRAS4B, HRAS, and NRAS. Of these three, KRAS is the most notorious and is found in the deadliest cancers including lung cancer, colorectal cancer, and pancreatic cancer.[1]

Darren Tomlinson, Ph.D. The Tomlinson lab at the University of Leeds is interested in using a novel molecular recognition tool, called an Affimer, to study protein function. An Affimer (also known as an Adhiron) is a scaffold protein that constrains two randomized loops for molecular recognition. They can be used as alternative reagents to antibodies for applications like diagnostics and used to probe the surface of target proteins to identify key domains involved in protein function. Tomlinson’s laboratory provides a service for screening against many types of molecules but our focus is using the Affimer scaffold to understand protein function at the molecular level.

Despite concerted efforts dedicated towards it in the last 30+ years, developing drugs that target KRAS has not been very successful. Considering the key role this driver oncogene plays, the pharmacological drugging of KRAS remains a real key challenge for cancer research.

Earlier this year, the U.S. Food and Drug Administration (FDA) approved sotorasib (Lumakras™; Amgen), a RAS GTPase family inhibitor, for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.  And while this drug represents a millstone in the treatment of patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer, it only tackles a small subset of the total number of cancers driven by RAS. [2]

A new way to target
Now researchers at the University of Leeds’ School of Molecular and Cellular Biology have found a new way to target a mutant form of the RAS protein has been referred to as the “Death Star” because of its ability to resist treatments and is found in 96% of pancreatic cancers and 54% of colorectal cancers.[3]

RAS is a protein important for health but in its mutated form, it can be switched on for longer, leading to the growth of tumors. The research team has found a new way to target the protein to pave the way for a greater range of treatments for more patients.

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“The RAS protein has been referred to as the Death Star with good reason and that’s because it’s spherical and impenetrable, essentially preventing drugs binding and inhibiting it. We’ve identified a further chink in the Death Star that can be used to develop new drugs beyond the ones already in development.” Darren Tomlinson, Ph.D., of the Astbury Centre for Structural and Molecular Biology and lead author of the report.

The researchers used the School of Molecular and Cellular Biology’s own patented Affimer biotechnology platform to pinpoint druggable “pockets” on the protein to allow effective treatment to take place.

The study was funded by the Wellcome Trust, the Medical Research Council, the Technology Strategy Board, and Avacta and is published in the June 30, 2021 edition of Nature Communications.

“This work opens up the door for the hundreds of other disease targets. We could effectively probe any protein involved in any disease for druggable pockets in the future,” Tomlinson added.

“Because it causes 20-30% of all known cancers, RAS really is the Holy Grail of therapeutic targets. The fact that it has previously been termed “undruggable” has allowed us to demonstrate the huge impact that our Affimer technology can have when it comes to treating challenging pathologies. We have already identified small molecules that bind to RAS, so it will be very exciting to be involved in developing these over the next few years,” explained Amy Turner, from the School of Molecular and Cellular Biology, who is a first co-author of the report and Ph.D. student.

The researchers say work on expanding more ways to target RAS is still in its early stages but they believe their discovery could lead to new treatments, putting Leeds at the forefront of the fight against cancer.

Highlights of Prescribing Information
Sotorasib (Lumakras™; Amgen)[Prescribing Information]
Docetaxel (Taxotere®; Sanofi Aventis)[Prescribing Information]

Reference
[1] Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016 Apr 1;129(7):1287-92. doi: 10.1242/jcs.182873. Epub 2016 Mar 16. PMID: 26985062; PMCID: PMC4869631.
[2] Novel Targeted Treatment For Patients With KRAS G12C-Mutated Lung Cancer Onco’Zine. June 4, 2021.[Article]
[3] Haza KZ, Martin HL, Rao A, Turner AL, Saunders SE, Petersen B, Tiede C, Tipping K, Tang AA, Ajayi M, Taylor T, Harvey M, Fishwick KM, Adams TL, Gaule TG, Trinh CH, Johnson M, Breeze AL, Edwards TA, McPherson MJ, Tomlinson DC. RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site. Nat Commun. 2021 Jun 30;12(1):4045. doi: 10.1038/s41467-021-24316-0. PMID: 34193876. [Article]

Featured image: University of Leeds, United Kingdom. Photo courtesy: © 2019 – 2021 University of Leeds, UK. Used with permission.

 

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