An oncogene is a gene that has the potential to cause cancer. In cancer cells, these genes are often mutated or expressed at high levels. Ras was the first oncogene discovered and is in one of the most frequently mutated gene families in human cancer. There are 3 forms of Ras: KRAS, HRAS, and NRAS. For over 30 years, cancer researchers have been trying to target Ras. Ras has been so difficult to block by a drug, that an entire initiative was developed.

Why has so much time been invested in this single protein? Ras is considered to be “undruggable”  when it is in its active formation. There is no place for a drug to bind almost like Ras is cloaked in a disguise. Researchers have tried to design drugs to bind here but have failed. One reason is that the drug that binds Ras would need to be so high in concentration that it would force Ras to bind to it instead of the protein complex known as Guanosine-5′-triphosphate (or GTP for short)  which is responsible for turning Ras into the active/ON formation. If researchers were able to inhibit Ras by increasing the concentration of the drug delivered to it, that brings up the question: are high doses of this inhibitor safe for people? No! Since the drug concentration would be so high, the patient is very likely to have adverse side effects. This has forced researchers to tackle this problem from a different angle.

To get a better idea of the genetic makeup of Ras, specifically KRAS since it is mutated in ~25% of cancers, researchers collected and screened biopsies from cancer patients and found that less than 20% of cancer patients with increased Ras protein have a single mutation from a G to a C  (for a glycine mutated to a cysteine at position 12). By making a crystal structure of KRAS at this single mutation spot and by using specialized computer software, scientists were able to reveal a new binding site. This information that this binding site provides can be used for drug development and can provide hope for patients.

Researchers at Amgen developed a drug called AMG 510 to specifically bind Ras and prevent it from changing into the active/ON formation. They then screened cancer patients for the KRAS G to C mutation and ran phase I clinical trials. They found AMG 510 to be safe for patients to take while used in combination with other common cancer therapies such as carboplatin or immune checkpoint blockade/therapy including anti-PD-1.  AMG 510 treatment resulted in decreased tumor size as well as increased the number of protective immune cells in lung cancer patients. This data shows that AMG 510 might be an effective anti-tumor agent in combination with anti-PD-1 therapy in patients with the specific KRAS G to C mutation.

Although these findings are limited to the small subset of cancer patients that must have this specific mutation, there is still a long way to go before AMG 510 can receive FDA approval and be commercially available. Still, the impact of these findings is really impressive! These data represent hope for what has been considered as hopeless as no cure for RAS mutations in cancers currently existed after over 30 years of research.

Peer edited by Aldo Jordan

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