Notorious KRAS: Taking down cancer researchers’ biggest foe

In June, the field held its breath as Amgen offered up its first data on AMG 510. The early results, released at a premier oncology meeting, included information on 35 patients, primarily with lung and colon cancer, all of whom harbored the G12C mutation and already had been treated with several other drugs. Despite the small data set, the excitement was palpable: not only was the drug safe, but it also prompted tumor shrinkage in half the 10 evaluable patients with lung cancer; 4 more saw their cancer stabilize.

The responses for colon cancer were less impressive, but KRAS researchers say they had always expected it to be a tougher disease to conquer. “Oftentimes people think a mutation is a mutation is a mutation,” Wellspring executive chairman Troy Wilson says. But, he explains, enough of the other players in KRAS’s signaling web have been drugged for researchers to know that some tumors are more recalcitrant than others.

Earlier this month, Amgen provided additional data supporting the early signs of efficacy in lung cancer, and later this month the firm will offer yet another trial update.

Investors, meanwhile, are obsessively parsing each tidbit of information that Amgen releases. Depending on whom you ask, each new data set either dampens or affirms the AMG 510 buzz. Investors’ primary concern is that the benefit offered by KRAS G12C inhibitors could be fleeting. Cancer is a pernicious foe, known to escape via side streets when a drug shuts down a main artery. Everyone is trying to understand if patients in the Amgen trial are already showing signs of resistance to the drug.

For investors, a shorter-term effect would mean lower sales of the drug. Although stock analysts say they have yet to put AMG 510 into their forecasting models, that hasn’t stopped them from estimating—using the early data from those few dozen patients—that the drug could bring in anywhere from $1.5 billion to $3.5 billion in annual sales.

The worries over resistance are not lost on researchers either. “Simply shutting off RAS is not always enough,” says Mark Goldsmith, CEO of Revolution Medicines, which is working on KRAS inhibitors with a different mode of action from the ones in the clinic. “There’s enough complexity and richness in the RAS cascade that there are workarounds available to the cell.”

Companies are using several strategies to address resistance. Some are simply trying to design better inhibitors. Mirati, for example, claims that it had a drug candidate that could have gone into the clinic a year before MRTX849 actually began trials, but it wanted to improve the drug’s properties.

“We’ve done a lot of preclinical work looking at this whole concept of rebound signaling,” Christensen says, referring to the idea that knocking out one signaling node could prompt cancer cells to shift their reliance to another. Because some of KRAS’s feedback pathways become “supercharged,” Mirati wanted to be sure its compound could bind to and block the protein over the course of a day. The firm ultimately landed on a compound with a half-life in the range of 20–30 hours, he says.

Researchers concede that compound design will get them only so far. They expect to see a proliferation of clinical trials combining KRAS inhibitors with other cancer drugs, including immunotherapies and other targeted small molecules.

One partner of interest is compounds that inhibit SHP2, a phosphatase that itself had been a tough drug target until it was recently conquered with allosteric inhibitors. As Christensen explains, SHP2 can affect the speed at which KRAS cycles between its on and off states. Because the current KRAS G12C inhibitors bind only to the inactive form of the protein, researchers reason that adding a SHP2 inhibitor would improve access to their target. Plus, he adds, “the two molecules are also good at comprehensively blocking downstream signaling.”

In July, Mirati and Novartis teamed up to conduct a study of MRTX849 and Novartis’s SHP2 inhibitor TNO155 in people with solid tumors harboring the G12C mutation. The combination is of interest to Revolution Medicines, which has a SHP2 inhibitor in two clinical studies and last year added a KRAS program through its acquisition of Warp Drive Bio.

Researchers also believe they can combine KRAS inhibitors with checkpoint inhibitors, immunotherapies that help immune cells spot and attack cancer cells. Next year, Amgen says, it will have data showing whether AMG 510 and a checkpoint drug that blocks PD-1 can kill tumors better than either drug alone.

Some believe a durable response will require therapies that can more broadly address KRAS. Moderna, for example, is testing a messenger RNA–based cancer vaccine that addresses the four most common KRAS mutations. In contrast to the years-long effort to find small molecules that block KRAS, the Moderna vaccine program went from “idea on a whiteboard to actually filing an IND”—an investigational new drug application—in roughly a year, says Moderna’s chief medical officer, Tal Zaks. Moderna partnered with Merck & Co. to develop the therapy both alone and in combination with Merck’s checkpoint inhibitor Keytruda.

“It always made sense with me scientifically to combine a cancer vaccine with a checkpoint inhibitor,” Zaks says. “If you’re going to immunize and get a whole bunch of T cells going, you want to make sure they’re unleashed and can go find cancer.”

The next tough targets

While they await more human data from KRAS G12C inhibitors, academic and industry researchers are pushing ahead with other ways to block members of the RAS family. The next targets on their list are the other two common mutants, G12D and G12V.

“The general consensus right now would be that targeting other specific mutants with the same kind of attack on the amino acid is going to be much more difficult than the one with cysteine,” UCSF’s McCormick says.

Because the current crop of drug candidates uses a chemical warhead targeting a cysteine only seen on G12C, chemists will have to come up with new strategies for broaching that same pocket on G12D and G12V.

Researchers at Boehringer Ingelheim, which has been working on KRAS inhibitors since 2012, recently revealed the first tool compound that can slip into a pocket that exists on both the active and inactive forms of KRAS. Darryl McConnell, research head for Boehringer’s site in Vienna, notes that significant work remains to make compounds potent and selective enough to bind to that pocket. “That pocket is druggable, no doubt,” he says, but the effort required to drug it will be intense. The pocket is “really small. It’s really shallow, and it’s really polar.”

Nevertheless, the advance is important. “We’ve got two pockets on KRAS that we’ve identified, which is two more than we had 10 years ago,” McConnell says. “How much can we exploit those pockets?”

“I don’t think it’s going to be easy—I mean, KRAS G12C wasn’t easy,” Amgen’s Cee says. “It might be possible.” Researchers now have the benefit of 6 or so years of work on the individual mutants, he says, giving them a sense of the protein’s flexibility, how it cycles between the active and inactive states, and its overall lifestyle.

All those lessons have been enough to get new players to invest in the field. Pfizer, for one, played up Array BioPharma’s vast KRAS knowledge when announcing its $10.6 billion acquisition of the firm. And patent filings suggest many other big firms are putting internal efforts into the protein family.

As Wellspring’s Liu points out, the KRAS G12C story shows that it takes only one good tool compound to open up the field. “If you can get that first step—find a small molecule and demonstrate cellular proof of concept—you can treat it as a normal drug discovery program.”

Company sources are reluctant to give even a whisper of their chemistry strategy for tackling the mutant everyone believes will be the next to be overcome, KRAS G12D. But efforts are definitely underway, and industry executives seem confident that drug candidates are less than 3 years away.

“There are important learnings from G12C in terms of the way the structure moves, the way the nucleotide cycles, the nature of the binding pockets that led us to believe that targeting other mutants is possible,” Mirati’s Christensen says. But, he cautions, KRAS G12D still has some “critical differences” that are presenting the firm’s scientists with a new learning curve.

Those who have been working on KRAS since the early days say they are gratified to see the field reach a tipping point. People no longer wonder whether someone is going to be able to conquer KRAS family members, UCSF’s McCormick says, but rather who will be the first to do it.

“It’s no longer undruggable; it’s a question of which drug is going to be the best,” McCormick says. “That’s a big ­difference.”