New promising Cancer Treatment

The recent approval of Lumakras (Amgen, AMG 510) by the US Food and Drug Administration as a treatment for non-small cell lung cancer is a breakthrough in cancer therapy. The drug acts as an irreversible inhibitor of KRAS, a mutant protein common to many troubling tumors, including lung, pancreatic and colorectal cancers.

KRAS has been the Moby Dick of cancer therapy. Over the last forty years, its elusive nature has stymied generations of drug developers. Discovered in 1983, it was one of the very first oncogenes ever identified. An oncogene is the mutated form of a normal human gene that often lies at the very origin of many cancers. KRAS is present in 32% of non-small cell lung cancers, 40% of colorectal cancers, and 85% to 90% of pancreatic cancers.

The normal cellular KRAS protein plays a central role in healthy cells by acting as an on/off switch for cell growth. KRAS is activated by binding to guanosine triphosphate (GTP). Once activated, the KRAS protein signals the cell to grow and divide. It is turned off when it converts GTP to guanosine diphosphate (GDP). The mutation that transforms KRAS into an oncogene locks the protein into an active state, permanently bound to GTP, causing cells to grow uncontrollably.

Why has KRAS been such a difficult problem to solve? Most drugs work by binding to sites within the crevices in a protein structure. According to Victor Cee, a research scientist formerly with Amgen,

There’s almost nowhere that a drug can stick to on that protein.” After screening a subset of chemicals, the team of researchers from Amgen found one that weakly bound to the KRAS molecule resting in a shallow pocket of the protein near the GDP binding site. Structural analysis showed that entry to a deeper crevice below was blocked by a histidine residue. Eventually, they found a family of drugs that could displace the histidine, thus allowing entry to the deeper cleft. Binding to this site alters the conformation of the nearby GDP binding site, fixing the GDP in place and permanently locking KRAS in the inactivated position.

Source: https://www.forbes.com/