The recent approval of Lumakras (Amgen, AMG 510) by the US Food and Drug Administration for the treatment of non-small cell lung cancer is a breakthrough in cancer therapy. The drug acts as an irreversible inhibitor of KRAS, a mutated protein that is common in many worrying tumors, including cancers of the lung, pancreas, and colon.
KRAS was the Moby Dick of cancer therapy. For the past forty years, its elusive nature has hampered generations of drug developers. It was discovered in 1983 and was one of the very first oncogenes ever identified. An oncogene is the mutated form of a normal human gene that is often the source of many cancers. KRAS occurs 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 (BIP). The mutation that turns KRAS into an oncogene locks the protein into an active state that is permanently bound to GTP, causing cells to grow out of control.
Why is KRAS such a difficult problem to solve? Most drugs work by binding to sites within the crevices in a protein structure. Victor Cee, a former researcher at Amgen, says, “There is almost nowhere that a drug can adhere to this protein.”
After screening a subset of chemicals, Amgen’s research team found one that binds weakly to the KRAS molecule, which rests in a shallow pocket of the protein near the GDP binding site. The structural analysis showed that access to a deeper crevice below was blocked by a histidine residue. Eventually they found a family of drugs that could displace the histidine, allowing entry into the deeper crevice. Figure 1 shows how Lumakras implant themselves in the now exposed crevice on the surface of the protein. Binding to this site changes the conformation of the nearby GDP binding site, fixes the GDP and permanently locks KRAS in the inactivated position. The position of the rotated histidine residue is shown in pink in the figure. Lumakras, shown in blue, binds covalently to the activating mutated amino acid cysteine, shown in yellow. The bound GDP is shown in white, red and dark blue. The green area in the figure indicates the location on KRAS that interacts with other cellular proteins.
KRas G12C bound to deoxyguanosine diphosphate (left) and AMG 510 (right). The pink region shows … [+]
Combining lumakras with additional medication may be needed to maximize the benefits of lumakras alone. Fortunately, with the advent of checkpoint inhibitors, there are several promising new drugs that can be combined with lumakras for more than one additive effect.
The accelerated FDA approval of this drug marks a new milestone not only for non-small cell lung tumors, but for many others, particularly pancreatic and colon tumors, for mutated KRAS. Screening tumors for mutated KRAS can open new avenues for cancer treatment and advance precision medicine by using the right drug for the right tumor.
The story of Lumakras is one of perseverance, determination and technical ability. As Amgen’s VP of Global Developments, Phuong Khanh Morrow, put it, “Taking on the KRAS challenge was a race against cancer for Amgen and the investigators participating in CodeBreaK’s clinical development program, and that race resulted in the fastest clinical trial program in the history of Amgen. Amgen believed in science and, given the high unmet need and limited treatment options, the Amgen team acted urgently to get Lumakras to patients as soon as possible. “
The effectiveness of this drug sets a precedent that could usher in new drugs that target other recalcitrant oncogenes. “KRAS mutations have long been considered resistant to drug therapy and represent a real unmet need for patients with certain types of cancer,” said Richard Pazdur, the FDA’s chief cancer drug evaluation officer, in a statement released by the FDA. Thanks to the new drug, help is now on the way.