For over 30 years, the protein KRAS is a major challenge in drug design. So far, there is no approved therapy for patients with KRAS mutations, which comprise around 25% of patients with lung cancer. It’s been on everyone’s “target” list as commonly mutated oncogene, while KRAS has earned a reputation in scientific circles as being “undruggable” because many pharmaceutical, biotech, and academic laboratories have failed to design a drug that successfully targets the mutant gene.
But recently , Dr. Kevan M. Shokat and his colleagues, in the Howard Hughes Medical Institute (HHMI) at the University of California, published an article entitled “KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions ” in the Nature journal, which aims for identifying and exploiting a novel “Achilles heel” in KRAs. They found “pocket”, or binding site, and designed a chemical compound that fits inside this pocket and inhibits the normal activity of mutant KRAS.
The above small molecules irreversibly bind to KRAS(G12C), subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Shokat said, “We report the discovery of a new pocket on KRAS that is druggable, and we believe this has real translational implications for patients.”
Additionally, Dr. Nathanael S. Gray, in the Department of Cancer Biology at the Dana-Farber Cancer Institute, reported the synthesis of a GDP analogue(SML-8-73-1) and a prodrug derivative (SML-10-70-1), which were selective, direct-acting covalent inhibitors of the KRAS (G12C) mutant relative to wild-type Ras. Biochemical and biophysical measurements suggested that modification of KRAS with SML-8-73-1 renders the protein in an inactive state.
What is KRAS protein?
KRAS, a member of Ras protein family, acts as a molecular on/off switch. When turned on , it recruits and activates proteins necessary for the proliferation of growth factor and ther receptors’ signal such as c-Raf and PI 3-kinase. In Combination with GTP, KRAS possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, and finally make itself turn off.
KRAS is one of the most frequently mutated oncogenes in human cancer. According to a discovery nearly 30 years ago, KRAS is mutated in 30 percent of human tumors, including 90 percent of pancreatic cancers, 40 percent of colon cancers, and 20 percent of non-small cell lung cancers. Cancers with Ras mutations are aggressive and respond poorly to standard therapies.
How to test KRAS mutations
The usual testing detects the seven common mutations in exon 2, codons 12 and 13, which account for up to 90-95% of KRAS gene mutations. While scientists would use variant methods without standardized regulations. It is noteworthy that Mayo Clinic’s Molecular Genetics Laboratory has recently introduced a KRAS mutation analysis assay (#89378 KRAS Gene, 7 Mutation Panel, Tumor Tissue) that tests for the common mutations in codons 12 and 13. As shown in the assay, concordance between the presence or absence of KRAS mutations in a patient’s primary tumor and corresponding metastatic tumors is high.
KRAS mutation testing may be performed on the primary tumor or a metastasis, and both are equally acceptable. The pathologist should select a tissue sample that is predominantly tumor and estimate the percentage of tumor cells in the sample. After all, direct sequencing, generally considered as the “gold standard” for KRAS mutation detection, requires a higher percentage of tumor DNA to reliably detect the mutation.
Treatment for cancer patients with KRAS Mutation
Some clinical trial data has suggested that patients with a KRAS mutation treated with chemotherapy and anti-EGFR therapy not only did not respond to the treatment, but had worse clinical outcomes than those treated with chemotherapy alone. There is currently no clear explanation for these findings.
Recent studies indicate that KRAS-normal tumors with a BRAF V600E mutation will also not respond to EGFR targeted therapy. This prompted National Comprehensive Cancer Network (NCCN) to update their guidelines to include optional BRAF mutation testing if KRAS results are normal.
EGFR is a therapeutic target for several other human tumors and Erbitux has been approved for use in certain head and neck cancers. However, KRAS mutation testing is not routinely recommended to guide treatment decisions for any other cancers.
1. KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013, 503, 548–551
2. Therapeutic Targeting of Oncogenic KRAS by a Covalent Catalytic Site Inhibitor. Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204.
3. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treatment Reviews. 2009,