The RAS Problem: Turning Off a Broken Switch
, by NCI Staff
Every year, more than one million people worldwide die from cancers driven by mutations in a gene called RAS. Despite the success in developing cancer therapies that target many genetic abnormalities that drive cancer, researchers have been unable to develop treatments that can directly target altered RAS proteins, and many have written off RAS as being “undruggable.”
Now, with new techniques in structural biology, biochemistry, imaging, and genomics—as well as focused funding support from NCI through the RAS Initiative—researchers are taking a new crack at this old problem.
Recently, Susan Bates, M.D., head of NCI’s Molecular Therapeutics Group and senior investigator in the Developmental Therapeutics Branch, and Frank McCormick, Ph.D., professor of cancer research at the University of California at San Francisco and co-director of the NCI RAS Initiative, presented a seminar about RAS oncogenes on the NIH campus.
RAS is the most commonly mutated oncogene in human cancers: mutations in RAS are present in 22 percent of all cancers, with the distribution varying widely by cancer type. Mutant forms of RAS are common in lung and colorectal cancers and are present in almost 95 percent of pancreatic cancers.
RAS actually represents a family of genes, each of which has distinct biological and clinical properties, Dr. McCormick explained. The first two, HRAS and KRAS, were discovered in the 1970s in the context of rat sarcoma viruses. The third RAS gene, NRAS, was later identified in human neuroblastoma cells.
RAS functions as an “on/off” switch for at least six downstream cellular signaling pathways that control growth and cell division. Several of these pathways, including the PI3K and MAPK pathways, are known to play important roles in cancer development and progression.
When a mutation occurs in a RAS gene, it can result in a mutant RAS protein that is permanently stuck in the “on” position, constantly activating downstream signaling pathways and promoting growth signals. In other words, said Dr. Bates, the mutant RAS protein is like a broken switch stuck in the “on” position—leading to uncontrolled cell growth.
The Role of RAS in Carcinogenesis
Although RAS is mutated in such a significant portion of cancers, its role in the development and progression of cancers is still being clarified.
For example, there is no difference in survival between lung cancer patients whose tumors carry a RAS mutation and those who don’t, noted Dr. Bates. In colorectal cancer, mutations in KRAS—which are present in 35 to 45 percent of patients—don’t appear to be the event that kick-starts cancer development, or carcinogenesis, she explained. These mutations tend to appear later on in the process, so KRAS’s role in driving carcinogenesis is not clear. Thus, it’s not clear whether inhibiting mutant KRAS proteins will be sufficient to treat cancers such as lung or colorectal cancer, she cautioned.
However, in pancreatic cancer—which generally has a very poor prognosis—KRAS mutations are among the first to occur during carcinogenesis, and they have an unambiguous role in driving this cancer, Dr. Bates said. A drug that can effectively target mutant RAS proteins, therefore, should be very valuable in treating pancreatic cancer.
Targeting the RAS Signaling Network
Because of RAS’s place at the nexus of several signaling pathways, drugs that target signaling molecules upstream of RAS, such as the epidermal growth factor receptor (EGFR), are ineffective against cancers driven by RAS mutations, explained Dr. McCormick.
Because mutant RAS proteins activate a suite of downstream pathways, a potential approach to treat cancers with mutant RAS proteins is to target multiple individual downstream pathways in combination (for example, with mTOR inhibitors and PI3K inhibitors). But often, these combination therapies are too toxic for patients to tolerate, he said.
An Elusive Target: Is RAS Still “Undruggable”?
NCI launched the RAS Initiative in 2013, in large part to overturn the thinking that targeting RAS is futile.
“I feel uncomfortable when I see the word ‘undruggable,’” former NCI Director Harold Varmus, M.D., told Nature at the time. “Everything’s druggable, we just need a concerted effort to get there.”
As part of the initiative, more than 50 researchers at the Frederick National Laboratory for Cancer Research (FNLCR)—and many more in the extramural research community—are working on understanding the basic molecular biology and biochemistry of RAS proteins.
One major effort involves elucidating the interactions between the RAS protein and its major downstream binding partner, RAF. Visualizing the three-dimensional structure of how the two proteins interact may provide clues about ways a targeted drug might be able to prevent mutant RAS from binding to RAF and thus thwart growth signals.
Another area of investigation focuses on the role of several “assisting” proteins, such as NF1, SPRED1, calmodulin, and others that recruit the relevant signaling partners to the cell membrane, where the RAS protein is located. Little is understood about how these proteins work, Dr. McCormick said, but a better understanding of their role could shed light on ways to block mutant RAS from sending downstream signals.
Scientists associated with the RAS Initiative are also focused on understanding the dynamics of the signaling networks in which RAS plays a role. Early studies characterized the signaling pathway as a linear cascade that proceeds in a logical, orderly fashion. But more recent studies have shown that the pathway is complex, with multiple feedback loops. In some cases, blocking one signaling molecule in the pathway can lead other pathways to compensate through a complex feedback mechanism, explained Dr. McCormick. This is why it is important to continue pursuing ways to target the mutant RAS protein itself, he said.
Several avenues for directly targeting RAS are being investigated. Dr. McCormick suggested that, using genetic engineering, it may be possible to silence expression of mutant RAS with small-interfering RNAs. And researchers at FNLCR are identifying proteins that are expressed specifically on the membrane of RAS-mutant cancer cells, with the goal of developing new immunotherapy approaches to help the immune system identify and kill cancer cells with RAS mutations.
Although he’s enthusiastic about the various possibilities, Dr. McCormick acknowledged that only time will tell which, if any, will bear fruit. “We’ll need to reassess the situation in a few years,” he said.