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Nature: Anti-cancer drugs are approaching some of the deadliest mutations

 Last Update: 2022-11-26
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Terri Conneran, a mother of three and a former corporate accountant in Charlotte, North Carolina, turned to people who had the same experience when she was diagnosed with lung cancer in 2017
.
Based on specific mutations found in human tumors, some groups have sprung up on social media
.

But Conneran was dismayed to discover that in her cancer, there was no such mutation in a gene called KRAS, and about a quarter of tumors had KRAS mutations
.
Part of the reason may be a lack of drugs
to target the mutation in this gene.
"People familiar with the matter say KRAS is not to be taken," Conneran said
.
So she started her own group, KRAS Kickers, and happened to do so
at the right time.

Last year, the U.
S.
Food and Drug Administration approved the first cancer therapy targeting kras, sotorasib (Lumakras), manufactured by Amgen, a biotechnology company based in Thousand Oaks, California
.
"It's the hope for pills," said Conneran, who has received funding from the pharmaceutical industry to support her team
.
"So we have patients alive
today.
" A second KRAS-targeted drug is expected to be approved
this year.

While the approval of sotorasib was a milestone, the drug targeted only one specific mutation of the KRAS protein, and its effects were short-lived: Most people who initially responded relapsed
months later.
On September 12, Amgen announced that the latest trial of sotorasib found that it only extended progression-free survival by about a month (a measure of how long a cancer progresses)
than standard chemotherapy.
Only 28 percent of participants treated with sotorasib responded
to it.
That's about twice as many people who respond to standard chemotherapy, but it still suggests that most people with KRAS-positive lung cancer won't get help
with new drugs.

Channing Der, a cancer biologist at the University of North Carolina at Chapel Hill, said that even so, the pace of KRAS research and the pursuit of KRAS targeted drugs have never been more active
.
The first signs of success suggest that it is possible to drug "non-resistant" KRAS, and now researchers in academia and industry are working on ways
to improve their methods.
"I've never seen this level of excitement and hustle
in the entire history of this field," he said.
"The current level is crazy
.
"

Fatal mutations

The KRAS protein is located at the center of the cobwebs of
key cellular pathways.
It plays a role
in controlling cell proliferation, cell death, and many things in between.
The KRAS protein circulates between the two conformations and switches from the "off" state to the "on" state
when it binds to the signaling molecule GTP.
Cancer-associated mutations make the protein more likely to stay in its "on" state and can be found
in almost all types of tumors.
This mutation is particularly prevalent in some of the deadliest cancers: for example, more than 80 percent of pancreatic cancers carry the KRAS mutation, and about 30 percent of lung adenocarcinomas and colorectal tumors carry the KRAS mutation
.

Sotorosib and a yet-yet-yet-approved drug, adagrasib (made by Mirati Therapeutics of San Diego, California), both target tumors
by attaching to the KRAS protein containing the G12C mutation.
This variation replaces the 12th amino acid in KRAS with cysteine (C), usually glycine (G).

This is the most common KRAS mutation found in lung cancer, but not the most prevalent KRAS mutation: Most KRAS mutation cancers, including Conneran's, have a different mutation at the same location, called G12D
.

This means that most people with KRAS mutation cancers still have no treatment
to target their mutation.
Conneran felt the frustration from the support group members
.
"That's the most common problem," she said
.
"Why didn't the G12C medication work for me? I'm
only one letter away.
’”

Another problem is that the response of this drug is erratic and short-lived
.
To date, clinical trials have been conducted in patients with advanced KRAS-driven cancer who have not responded to
other therapies.
In these participants, treatment with sotorasib stopped tumor growth
for a little over 6 months.
Less than one-third of patients with G12C lung cancer and less than one in ten patients with G12C colorectal cancer respond to
sotorasib2 treatment.
After treatment, many tumors
developed resistance to this drug.
Alex Adjei, an oncologist at the Cleveland Clinic in Ohio, said, "Because it's so difficult to suppress KRAS, our enthusiasm is actually out of proportion
to the data itself.
"

Target G12C

Nevertheless, the initial success of G12C drug therapy has breathed life
into the field.
That's partly because of renewed hope: drugs that target other KRAS mutations can be found, including G12D
.
Kevan Shokat, a chemical biologist at the University of California, San Francisco, said the decision to target G12C was crucial to the success of sotorasib, which his lab laid the groundwork
for sotorasib in 20133.
Shokat also co-founded Redwood City, Calif.
-based Revolution Medicines, which is developing therapies
to inhibit KRAS.
Cysteine is more chemically active than many amino acids, making it easier to design drugs
to bind to.

KRAS inhibitor trial

Dozens of drug trials targeting the KRAS protein have been registered
on the U.
S.
registry center clinicaltrials.
gov.
Most are for cancers that carry G12C mutations, but some groups have begun testing G12d-targeted drugs and other approaches
.

drugs	target	The manufacturer's country	Number of trials	state
Sotorasib	G12C (target "off" state of mutant protein)	Amgen Corporation of America	31	It has been approved for the treatment of non-small cell lung cancer.
Adagrasib	G12C	Mirati Therapeutics, USA	14	Phase III clinical trials comparing with other drugs are ongoing .
Injection - 21822	G12C	Jacobio, China	5	Phase I/II trials began at several sites in the United States and China.
d - 1553	G12C	InventisBio, China	4	Phase I/II trials began worldwide.
Hours - 4642	G12D	Jiangsu Hengrui Pharmaceutical, China	1	Phase I trials have not yet been recruited .
ASP3082	G12D	Astellas Pharma, Japan	1	Phase I trials began at several U. S. locations .
rmc - 6236	Multiple RAS mutations (target protein's 'on' state)	Revolution Medicines, USA	1	The trial ruled out people with the G12C mutation.

Frank McCormick, a cancer biologist at the University of California, San Francisco, is the co-founder of Bridge Bio in Palo Alto, Calif.
, which is also developing KRAS inhibitors
.
As molecules are able to enter small pockets of protein 3D structures that bind to cysteine, he said, researchers have a starting point from which to design drugs
that can bind to other amino acids.
Scientists are also looking for molecules
that can bind to different forms of protein as they cycle between their on and off states.
Sotorasib binds exclusively with the OFF form, which may limit its potency
.
"The story of KRAS G12C tells us that if you had a brilliant chemist, you might be able to give other drugs that can't be treated," said
Patricia Lorosso, an oncologist at Yale University School of Medicine in New Haven, Connecticut.
"However, it's not enough to just drug, you have to go further
.
"

McCormick said that in 2021, researchers at Mirati reported a compound called MRTX1133, which binds to G12D, but the chemical properties of the molecule make it difficult to use
as a drug.
The company has reformulated the compound and plans to conduct clinical trials
.
Even if these studies are unsuccessful, he said, the original molecule has been a key tool
for researchers to explore ways to inhibit mutants.
"This is another major leap forward
in the field.
"

Sotorasib's selectivity for mutant KRAS could be a safety advantage: Because KRAS involves so many key cellular pathways, many researchers worry that drugs that inhibit normal KRAS could be toxic
.
But despite these potential concerns, some researchers are exploring drugs that can shut down all KRAS proteins, whether mutant or wild
.

Unpublished data from mouse experiments suggest that doing so may be safe — cells can recruit related proteins called NRAS and HRAS to fill some of the functions of
the blocked KRAS protein.
"The big question is, 'Does wild type matter?'" McCormick said
.
"But most people aren't too worried
.
"

NRAS and HRAS may help kras-mutated tumors avoid the effects of drugs like sotorasib, which has led some researchers to explore "pan-RAS inhibitors"
that block all three proteins.
Kwok-Kin Wong, a lung cancer expert at NYU Langone Health Center in New York City, said there is controversy
over whether the drugs are safe.
"Everyone and their grandmothers are expecting what will happen
," he said.
"There has to be some price to pay, I just don't know what the price
will be.
"

Meanwhile, efforts to make G12C inhibitors more effective by combining them with other anti-cancer drugs are ongoing, with mixed results
.
Researchers are particularly optimistic
about the combination of sotorasib and drugs that release the immune system to fight tumors (checkpoint inhibitors).
Preclinical data in mice suggest the two would be a powerful combination, but Amgen announced in August that its earlier studies showed a high
incidence of liver toxicity in humans.

Loruso said the chemistry of Sotorasib itself could complicate the combination
.
Researchers often reduce the dose of the combination to minimize the toxicity of taking both drugs at the same time, but the toxicity of sotorasib does not decrease
linearly with the dose, she said.
"At half the dose, you may not be able to avoid many of the toxicities
you see at high doses.
"

Mirati has said its G12C inhibitor adagrasib does not cause serious side effects when used in combination with immunotherapy drugs, and researchers are eagerly awaiting publication of those results, McCormick said
.
"The preclinical data in mice is shocking," he said
.

Drug resistance

Shokat and his collaborators are looking for other ways to activate the immune system
in KRAS-driven cancers by harnessing the covalent bond formed between the KRAS protein and an inhibitor compound similar to sotorasib.
This complex can be broken down by cells and presented to the immune system
on the surface of cells.
Shokat's team recently tested an engineered antibody that recognizes this foreign fragment and found that it triggers immune cells to kill G12C cancer cells in culture—including cells
that are resistant to the inhibitor treatment alone.

Other studies aim to expand the effectiveness
of sotorasib and other KRAS drugs by preventing or slowing the emergence of resistance.
Yao Wantong, a cancer biologist at the University of Texas Anderson Cancer Center in Houston, said that despite decades of research on KRAS, these immune mechanisms have only now come into focus
.
Much of the research has been based on models, such as mice, where the KRAS gene is deleted (or "ablated"
).
"We are uncertain whether the response of KRAS inhibitors is similar or different from genetic ablation," she said
.
"We need to understand the mechanisms of
drug resistance as soon as possible.
"

Some clinical trials are combining KRAS inhibitors with therapies that block other components of the signaling pathway controlled by this protein
.
This approach has also been successful in treating some other cancers, such as colon tumors
with mutations in the BRAF protein.
But KRAS-driven cancers can be particularly daunting, Der said: Resistance to KRAS inhibitors appears to be extraordinarily complex, with some people having multiple resistance pathways
in a tumor.
"We now have a preliminary understanding of the mechanisms of drug resistance," he said, "and I think it's kind of alarming
.
" ”

Some joint trials are underway, and it's too early to predict which will succeed, Der said
.
The combination of sotorasib with a drug that inhibits another protein called EGFR may improve the efficacy
of kras-targeted drugs for colon cancer, he said.
But early unpublished clinical data from another combination — the binding of sotorasib to a drug that blocks a protein called SHP2 — failed to live up to expectations
.
"It's still early," Der said
.

Wong said that while all of this suggests that researchers still have a long way to go, it doesn't diminish the achievement
of eventually drugging KRAS that can't be taken.
The concern, however, is that enthusiasm for this landmark scientific achievement will be misunderstood by kras-driven cancer patients, Adjei said
.
"It's a good balance," he said
.
"You want to give hope and show that they're making progress, but at the same time, you don't want it to sound like we've cured the KRAS-mutant cancer
.
"

For her part, Connorand is well aware of the complexities
of her cancer.
Despite having no scientific background, she can now name KRAS mutations and potential combination therapies in one sitting, while also pausing to acknowledge warnings and holes
in the data.
"It's complicated," she said
.
"But, you know what? Hopefully, too
.
”

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