STUDIES OF CANCER-CAUSING VIRUSES in rats in the 1960s ultimately led to the identification of three human RAS (for RAt Sarcoma) genes. When mutated, these genes can drive human cancer cells to proliferate wildly, invade normal tissues and disseminate throughout the body.
The protein products of mutated RAS genes have long been a logical target for cancer treatment. If a drug could be devised to interact selectively with defective RAS proteins, malignant cancer progression could be slowed or even stopped.
Mutant HRAS, KRAS or NRAS genes have been found in 20% to 30% of all human cancers. Pancreatic cancers are particularly addicted to RAS gene defects, with more than 90% of pancreatic cancer cases carrying mutations in KRAS. These mutations also appear in as many as 45% of colorectal cancers and 20% of lung cancers.
The proteins encoded by the RAS genes function as cellular switches to regulate a wide array of functions in response to external signals. Located at the cell membrane near the receptors for such signals, the RAS proteins normally shuttle between on and off states via binding guanosine nucleotides, which are small, specialized sugar molecules. When RAS proteins are mutated in cancer cells, they remain in the on state, promoting many of the most malignant cell behaviors.
For all too long, defective RAS proteins locked in the on state have been considered undruggable because no one could find a pocket in which to tuck a small molecule drug to turn the protein off. This frustration prompted Harold Varmus, then director of the National Cancer Institute, to launch the RAS Initiative in 2013 to energize the most creative minds in drug discovery to devise new approaches to RAS drug targeting. The race was on to find RAS drugs.
Almost straight out of the block, Kevan Shokat, a chemical biologist at the University of California, San Francisco, discovered a drug-like molecule that could bind to mutant KRAS proteins where the normal sequence of amino acids has been altered—a glycine (G) has been replaced by a cysteine (C) at position 12 (called G12C). Improved versions of this molecule from Wellspring Biosciences, along with similar drugs from Amgen and Mirati, have shown promising benefits in preclinical studies and in early clinical trials. The Amgen drug, Lumakras (sotorasib), has already been approved by the Food and Drug Administration (FDA) for treatment of non-small cell lung cancers carrying KRAS G12C mutations. Mirati’s drug, adagrasib, is currently under scrutiny by the FDA.
Could these drugs finally deliver effective treatments for pancreatic cancers? Alas, despite the excitement the new drugs have generated, targeting KRAS G12C will not benefit most pancreatic cancers even with their KRAS addiction. In pancreatic cancers, the glycine at the 12th amino acid in KRAS is replaced by aspartic acid (41%), valine (24%) or arginine (16%). Nevertheless, with the insights gained by creating KRAS G12C drugs, newer drugs targeting these other mutant RAS proteins are not far behind, offering new hope for treating many different human cancers.
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