by Dr. C.H. Weaver M.D. June 2019
Decades of research may have finally determined how to target KRAS, a major genetic driver of cancer. Initial study results presented at the 2019 American Society of Clinical Oncology's annual meeting in Chicago revealed that the novel precision cancer medicine currently known as “AMG 501” caused cancers to shrink in five of 10 lung cancer patients.
KRAS, an oncogene that impacts the growth of lung, pancreatic and colorectal cancers. The new medication is the first of its kind to reach clinical testing and works by binding to what researchers describes as a "hidden groove" on the protein produced by the mutated KRAS gene. When AMG 510 binds, the protein is inactivated which “turns off” the signals it sends to trigger cell division and cancer cell growth. AMG 510 is aimed at a specific type of KRAS mutation called G12C, which occurs in roughly 13% of non-small cell lung cancers, 3% to 5% of colorectal cancers, and between 1% and 3% of other cancers.
So far, 35 patients have enrolled in a Phase 1 clinical trial and the medication appears well tolerated with acceptable side effects so far….
Among 10 lung cancer patients with the KRAS G12C mutation confirmed by gene sequencing five individuals experienced a partial response to therapy and four had stable disease. All patients who responded remain on therapy with follow-up stretching from seven weeks to more than six months. Interestingly, results didn't appear as positive in colorectal cancer, however, where 13 of 18 evaluable patients had stable disease.
A Little More Information About the KRAS Oncogene
A pivotal milestone in cancer research was the discovery of a group of genes called the RAS family. RAS is an oncogene—a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. These genes are intricate players in the normal cell cycle, responding to cues both outside and inside the cell that regulate how fast a cell should grow and divide. Furthermore, there are myriad proteins that interact with RAS—including receptors on the cell surface—that pass signals into the cell through complex circuits of protein interactions, with the end result being changes in gene expression. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer.
There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer, KRAS is the most frequently mutated oncogene in human colorectal cancer. About 40 to 50 percent of human colorectal cancers have mutated KRAS genes. Recently developed laboratory assays are able to differentiate those tumors that have this mutation from those that have normal (also called wild-type) KRAS.
This has had several therapeutic implications. Cancers that have non-mutated, or wild-type, KRAS are susceptible to a class of biologic agents called epidermal growth factor receptor (EGFR) inhibitors. EGFR is a receptor on the surface of the cell that binds to a growth factor called epidermal growth factor (EGF). This receptor activates cellular pathways that promote cell growth and division, with KRAS being one of the key players in the process. Blocking the EGF receptor removes this important signal for the continued growth of cancer cells. The two EGFR-targeting agents studied in colon cancer are Erbitux® (cetuximab) and Vectibix (panitumumab).
Another exciting group of drugs that specifically targets the KRAS protein works by inhibiting an enzyme called farnesyltransferase. This enzyme is involved in activating the RAS proteins. As of yet these drugs are not available for use at the bedside and are currently being tested in animal models.