Two-Drug Combo Targets KRAS and Fights Resistance

New therapies for cancers with once-tough-to-target mutations in the KRAS gene are starting to gain traction.

KRAS amplifies signaling pathways that lead to oncogenesis, the very complex, multi-step process by which normal cells mutate into cancerous cells, leading to uncontrolled cancer growth. Drugs called KRAS inhibitors attempt to shut down that process.

One hurdle facing researchers is that cancer patients eventually face the risk of treatment resistance. So scientists are looking at ways to make sure treatment resistance never gets the chance to gain a foothold. That’s the idea behind a new study published in the journal Cancer Research from a team at the University of California San Diego School of Medicine.

In the study, the scientists looked at combination treatment featuring a drug called afatinib, an ERBB gene family inhibitor, along with the KRAS inhibitor MRTX1133, which is in clinical trials for KRAS G12D-mutated cancers. The team showed that the combo reduced resistance; it also improved survival in mouse models of pancreatic cancer. The team discovered this drug combination was also more effective at clearing tumors than either drug was alone. 

A Synergistic Effect

In a study presented at the 2022 American Society for Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, patients with pancreatic cancer had a 50 percent objective response to the drug adagrasib, a clinically approved KRAS G12C inhibitor. The drug worked more effectively in pancreatic cancer patients than those with other GI malignancies.

But the drug was only tested as a single agent, “and we know that patients are going to eventually develop resistance, which is why we need to look at combinations,” explains Hervé Tiriac, Ph.D., co-senior author on the Cancer Research study and assistant research scientist at UC San Diego Health. “Pancreas cancer is a very tough disease to treat with the current drugs we have available. So when drugs like adagrasib and MRTX1133 come along, it’s very exciting.

“But the issue remains that the drugs are going to eventually stop working. Our hypothesis was what drugs do we have available that may be better in combination to stop resistance. That’s what no one was really looking at.”

A Complicated Loop

Research shows there are numerous pathways to KRAS drug resistance. One of those pathways involves a specific set of genes called ERBB that are involved in cell growth, division, migration, and apoptosis, or cell death.

But things get a little complicated when it comes to KRAS inhibition, according to prior research conducted by Tiriac’s team. ERBB receptors communicate with KRAS to send signals. Generally, “the communication between ERBB and KRAS is a kind of feedback loop that keeps things stable,” Tiriac explains. When KRAS is turned off, which happens when a KRAS inhibitor comes into play, those receptor proteins start to pile up, and when the drug runs out and KRAS is no longer inhibited, their expression is stimulated and KRAS is again leading the charge in oncogenesis. Simply put, when KRAS goes down, ERBB goes up and drives KRAS and other related genes back up again.

“This [study] shows that KRAS inhibitors can change how genes are regulated,” Tiriac notes. “Turn KRAS off with an inhibitor, those ERBB proteins accumulate upstream. It’s like a massive burst of proliferation. That makes everything worse, because there are so many more receptors.”

Finding a Potential Solution

The team began with a screening assay on small molecules. They then tested results on pancreatic cancer cell lines and 3D organoids. “With afatinib there’s a permanent bond with the ERBB receptors. So it shuts down completely. It’s not reversible,” Tiriac says.

The researchers also tested the drugs in a live mouse model of pancreatic cancer and found that mice treated with both drugs survived significantly longer than those treated with either drug alone. Generally, those mice would die within a few weeks after tumor cell grafting.

For mice that hadn’t yet developed resistance to MRTX1133, the afatinib–MRTX1133 combo prevented resistance from developing and shrank tumors more effectively than either agent alone. “That’s the synergy,” Tiriac explains. “Both drugs work better together in improving initial response.”

“We now know the mechanism, and that means that potentially you don’t have to wait for resistance to develop to think about choosing this combination. Using it upfront was actually very effective.”

Among mouse models that had already developed resistance, the drug combination also halted tumor growth. Treatment using afatinib alone did not halt tumor growth, again suggesting that giving the drugs together was the most effective approach.

All Models Benefit

The drug combo was very effective in all models used by the researchers. All mice that received the combination treatment outlived mice that received only one agent. Among mice receiving combo treatment, some lived as long as 60 days, while mice in other cohorts died before day 40. “All these mice eventually did die, and that’s important to say,” Tiriac adds. “This is not a cure for pancreatic cancer.”

“But we are definitely on track to make an impact on survival of patients, and it could be a game changer. Maybe patients won’t be cured, but survival should be pushed dramatically. It’s things like this that give us all hope. There are other labs combining KRAS inhibitors with immunotherapy and others studying different combinations which could be curative. It’s an exciting time in the field. But we have a lot of work to do.”