KRAS protein mutated in many cancers is considered "untreatable". Now, scientists hope to save lives with a batch of new compounds targeting it.
Scientists have been working to design a drug that interacts with the relatively smooth surface of KRAS protein
Conneran, a mother of three in Charlotte, North Carolina, and a former company accountant, who sought support from people who experienced the same thing when she was diagnosed with lung cancer in 2017.
She was frustrated to find that there was no such gene in her cancer, in a gene called KRAS, which mutated in about a quarter of all tumors.
Last year, the U.S. Food and Drug Administration approved the first KRAS-targeted cancer therapy - Sotolassib, manufactured by Amgen, a biotech company in Thousand Oaks, California.
"It's hope for the drug," Conneran said, who received funds from the pharmaceutical industry to support her team. "So we have patients alive today. The second KRAS-targeted drug is expected to be approved this year.
Although the approval of sotolasib is a milestone, the drug targets only one specific mutation in the KRAS protein, and its effect is short-lived: Most people who initially respond relapse after a few months.
On September 12, Amgen announced that the latest trial of sotolasib found that it extends progression-free survival, an indicator of the time when cancer does not worsen, only about a longer than standard chemotherapy. One month.
Only 28% of participants who received sotolasib treatment responded to this. This is about twice the number of people who responded to standard chemotherapy, but it suggests that most people with KRAS-positive lung cancer will not get the help of new drugs.
Even so, the pace of KRAS research and the pursuit of KRAS-targeted drugs have never been so vibrant, Cancer biologist Channing at the University of North Carolina at Chapel Hill Der said.
Now researchers in academia and industry are developing ways to improve their approaches, with the potential for drug treatment of “untreated” KRAS.
fatal mutation
KRAS protein is located at the core of the key cellular signaling pathway. It plays a role in controlling cell proliferation , cell death, and many things in between. The KRAS protein circulates between two conformations, switching from “off” to “on” when it binds to the signaling molecule GTP.
cancer-related mutations make protein more likely to linger in its "open" state and can be found in almost all types of tumors. This mutation is particularly common in some of the deadliest cancers: for example, more than 80% of pancreatic cancer carry KRAS mutations, as are about 30% of lung adenocarcinoma and colorectal tumors.
sotorosib and a yet-approved drug adagrasib (by Mirarti, San Diego, CA Therapeutics manufactured) all target tumors by attaching to a KRAS protein containing a mutation called G12C.
This variant replaces the twelfth amino acid in KRAS with cysteine (C), usually glycine (G). It is the most common KRAS mutant found in lung tumors, but is not the most common KRAS mutant in general: most KRAS Mutant cancers, including those of Conneran, have different mutations in the same location called G12D.
This means that most people with KRAS mutant cancer still have no treatment for their mutations. Conneran felt the frustration of the support group members. "This is the most common question," she said. "Why doesn't the G12C drug work for me? I'm only one letter away.
Another problem is the incomplete, short-term response of the drug.
So far, clinical trials have been conducted in advanced KRAS-driven cancer patients that have not responded to other therapies.
Among these participants, sotolasibu treatment prevented tumor growth for more than six months. Less than one-third of patients with G12C lung cancer and less than one-tenth of patients with G12C colorectal cancer responded to sotolasibu treatment.After treatment with
, many tumors become resistant to drugs. “Because it’s very difficult to suppress KRAS, our enthusiasm is actually disproportionate to the data itself,” said Alex Adjei, an oncologist at the Cleveland Clinic in Ohio. "Nevertheless, initial success in G12C drugs has injected vitality into the field. The decision to target G12C is crucial to the success of Sotolasibu," said Kevan Shokat, a chemical biologist at the University of California, San Francisco. His lab laid the foundation for Sotolasibu in 2013.
Shokat also co-founded Revolutionary Drugs, a Redwood City, California-based company that is developing treatments that inhibit KRAS. cysteine is more chemically reactive than many amino acids, so it is easier to design drugs to bind to them. "As molecules can adapt to tiny pockets in the 3D structure of proteins to bind cysteine, researchers have a starting point to design drugs that can bind other amino acids," said Frank McCormick, a cancer biologist at UC San Francisco, who is also co-founder of Bridge Bio in Palo Alto.
California , also developing KRAS inhibitors. Scientists are also looking for molecules that can bind to different forms of proteins when circulating between the on- and off states of proteins. Sotolasibu is specifically combined with closed forms, which may limit its effectiveness.
"The story of KRAS G12C tells us that if you have an extraordinary chemist, you might give other incurable medicines," said Patricia LoRusso, an oncologist at Yale School of Medicine at New Haven, Connecticut. "However, just drugging it is not enough, you have to push it forward."
2021, Mirati researchers reported that a compound called MRTX1133 binds to G12D, but the chemical properties of the molecule make it difficult to administer as a drug.
The company has reformulated the compound and plans to initiate clinical trials. Even if these were not successful, primitive molecules have been a key tool for researchers to explore ways to inhibit mutants. This is another major leap in the field.
Sotorasib's selectivity for mutant KRAS may be a safe advantage: Because KRAS is involved in many key cellular pathways, many researchers are concerned that drugs that inhibit normal KRAS will be toxic. But despite these potential concerns, some researchers are exploring drugs, mutants and wild types that shut down all KRAS proteins. Unpublished data in
mice suggest that it may be safe to do so. Cells can recruit related proteins called NRAS and HRAS to fill in certain functions of blocked KRAS proteins.
NRAS and HRAS may help KRAS mutant tumors avoid the effects of drugs such as sotolasib, leading some researchers to explore "pan-RAS inhibitors" that block all three proteins.
There is a controversy over whether these are safe, said Kook-Kin Wong, a lung cancer expert at the New York University Langone Health Center in New York City. "Everyone is very much looking forward to what will happen, but we don't know what will be."
At the same time, efforts to make G12C inhibitors more effective by combining them with other anti-cancer drugs are underway, but the results are mixed.
Researchers are particularly optimistic about the combination of sotolasippi and drugs that release the immune system against tumors, called checkpoint inhibitors. Preclinical data 5 suggests that the two will be a powerful combination in mice, but Amgen announced in August that its early studies showed a high rate of hepatotoxicity in humans.
This combination may be complicated by the chemical properties of sotolasib itself. Researchers often reduce the dose of combination drugs to minimize the toxicity of exposure to both drugs at the same time, but the toxicity of sotolasib does not decrease linearly with its dose. "At half the dose, you may not be able to circumvent the many toxicities you see with higher doses," LoRusso said."H
Mirati said its G12C inhibitor Adagrasib does not cause serious side effects when used in combination with immunotherapeutic drugs, and the researchers eagerly await the publication of these results, McCormick said. "The preclinical data in the mice are shocking," he said.
foreign fragment
Shokat and his collaborators are looking for other ways to leverage the covalent bond formed between the KRAS protein and the inhibitor compound similar to sotolasib to engage the immune system in KRAS-driven cancer.
This complex can be broken down by cells and presented to the immune system on the surface of the cell. Shokat's team recently tested an engineered antibody that recognizes the foreign fragment and found that it triggers immune cells to kill G12C cancer cells in cultures , including cells treated with only inhibitor .
Other studies aim to expand the effectiveness of sotolasib and other KRAS drugs by preventing or slowing the advent of drug resistance. But despite decades of research on KRAS, these resistance mechanisms are now in the spotlight, says Wanton Yao, a cancer biologist at the MD Anderson Cancer Center of the University of Texas, Houston. Most of the research is based on models, such as mice, where the genes of KRAS have been deleted (or “ablated”). "We are not sure if the response to KRAS inhibitors is similar or different to genetic ablation," she says. "We need to understand the mechanisms of drug resistance as soon as possible.
Some clinical trials are combining KRAS inhibitors with therapies for other components of signaling pathways that block protein control. This approach has successfully treated some other cancers, such as colon tumor with BRAF protein mutations.
But KRAS-driven cancers can be particularly daunting, Der said: Resistance to KRAS inhibitors seems unusually complex, and some people have multiple resistance pathways in one tumor. "We now have a glimpse of the resistance mechanism," he said. "I think it's a little shocking.
Der said several combined trials are underway, and it's too early to predict which trial will succeed. He said the combination of sotolasci with a drug that inhibits another protein called EGFR may improve the efficacy of KRAS-targeted drugs in colon cancer .
But, early, unpublished clinical data from another combination - sotolasci with a drug that blocks a protein called SHP2 - Failed to meet expectations. “It’s too early,” Der said.
While all of this suggests that researchers have a long way to go, this doesn’t undermine the achievement of ultimately drugging KRAS that is untreated. However, a concern is that passion for this landmark scientific achievement will be misunderstood by KRAS-driven cancer patients. “It’s a good balance and we want to give hope and show that they are making progress, but at the same time, we don’t want it to sound like we’ve cured the KRAS mutant cancer.
As far as Conneran is concerned, she understands the complexity of cancer. Despite her lack of scientific background, she is now upset about KRAS mutations and potential combination therapy, pausing to acknowledge warnings and vulnerabilities in the data. “It’s complicated,” she said. "But, you know? Hopefully so.
