New Drug Combination Targets KRAS Mutations in Lung Cancer
A team of researchers at Moffitt Cancer Center has found a new drug combination that could help overcome resistance in a tough-to-treat form of lung cancer. They shared their findings at the American Association for Cancer Research annual meeting.
About one in four lung cancers are driven by mutations in the KRAS gene. This gene is part of the larger RAS family, which acts like an on/off switch for cell growth. When working correctly, these genes help regulate how cells grow and divide. But when KRAS mutates, it causes cells to grow uncontrollably and form cancer.
Eric Haura, MD
“They're like a gas pedal stuck in the on state,” explained Eric Haura, MD, associate center director for Clinical Science and director of the Lung Cancer Center of Excellence.
The drug sotorsib was developed to target patients with a specific mutation known as KRAS G12C. Sotorsib can shrink tumors by blocking the mutation that helps cancer grow. However, many patients become resistant to the treatment over time.
“Patients typically relapse in six to 12 months. So, what we wanted to study is why people are relapsing and what can be done about it,” Haura said.
To tackle this problem, the team tested a new approach. They used two experimental drugs on patients who had become resistant to sotorsib: one drug targets the KRAS G12C mutation, while the other drug focuses on several versions of RAS proteins.
“We have developed models in the lab that mimic what happens in humans and used combinations of RAS inhibitors — compounds that target different forms of KRAS proteins — to show you can overcome resistance by combining two RAS inhibitors.”
When used together, the drugs shrank tumors and slowed cancer growth more effectively than either drug alone. Based on these results and other supporting research, a clinical trial is now underway at Moffitt to test this two-drug strategy in patients.
“I think the message is one of incredible hope for patients,” Haura said.
Moffitt is rapidly expanding its portfolio of clinical trials targeting RAS-mutant cancers, accounting for up to 30% of all cancers. From lung and pancreas cancers to colon cancer and melanoma, multiple early-phase studies are now underway or in development, including several first-in-human trials targeting different forms of the RAS protein.
“We need to get out there, find the best drugs and sponsors, and bring those agents in as quickly as we can,” Haura said. “It’s also important that people in the community understand if they have cancer with one of these RAS mutations, they should be seeking out clinical trials testing new agents that directly target RAS.”
