This gene mutation — present in up to 30% of cancers — fuels cancer growth.
A specific gene known as KRAS plays an important role in directing how your cells grow, mature and die off in an orderly, preprogrammed fashion. But when the KRAS gene becomes changed or mutated, cells can grow uncontrolled and don’t die off when they should, resulting in cancer. Dozens of such genes, known as oncogenes because they aid the development of cancer, have been identified since the 1970s, and cancer drugs designed to target the function of these genes are often referred to as targeted therapy or precision medicine.
Found in up to 30% of all cancers, KRAS mutations are prevalent in cancers such as colorectal, lung, pancreatic and leukemia. Cancers that have KRAS mutations are often more difficult to treat, don’t respond as well to standard therapies, are more likely to spread and have poorer prognosis. More than half of colorectal cancers and 90% of pancreatic ductal adenocarcinomas (the most common type of pancreatic cancer) have KRAS mutations.
From undruggable to treatable
While KRAS was discovered to be an oncogene in 1983, finding a way to target it proved elusive, and the mutation was deemed “undruggable” for decades. A breakthrough was finally reached in 2021 when the first drug to target KRAS, sotorasib, was FDA approved in 2021 for treating non-small cell lung cancer. Patients at Roswell Park Comprehensive Cancer Center had early access to the drug through clinical trials.
However, KRAS mutates in different ways and sotorasib only targets the KRAS mutation known as G12C. “There remains a need for additional KRAS-targeting drugs to provide other treatment options for patients who do not respond — or who develop resistance — to the drug,” says Christos Fountzilas, MD, FACP, Associate Professor of Oncology and Associate Director for Solid Tumors, Early Phase Clinical Trials Program at Roswell Park.
New agents target KRAS in different way
Roswell Park now has clinical trials of two new KRAS-targeting agents that work differently than sotorasib. The KRAS gene produces a protein that relays messages to the cell signaling when to grow and multiply. The protein acts as an ‘on-off’ switch for the signal. When it’s ‘on’ it activates the cells to multiply, grow and metastasize. Where the drug sotorasib worked to keep the switch in the ‘off’ setting, these new agents work differently.
“The agent in my trial takes a different approach,” explains Dr. Fountzilas. “It binds to the KRAS molecule and breaks it down. It switches the power off by ‘cutting the wire,’ and no signal gets through to tell the cell to grow.” This phase 1 trial is for patients with advanced pancreatic, colorectal and lung cancer that have the KRAS mutation called G12D.
Another clinical trial, headed by Roswell Park medical oncologist Kannan Thanikachalam, MD, involves a new agent designed to target any of the KRAS mutations in patients with advanced bile duct cancer. This trial studies a new agent in combination with the drug trametinib, which blocks an abnormal protein from telling the cancer cells to multiply. The new agent in this study, ezurpimtrostat, aims to interfere with a housekeeping process that cancer cells use to survive — where they break down to remove, replace or recycle their own damaged parts. The idea is that using these two agents together could fully block the growth of the cancer cells. “If this trial shows that this combination is safe and effective, it would be a significant step in improving outcomes for patients,” says Dr. Thanikachalam.
“We screen every patient with pancreatic, lung, or colon cancer for KRAS mutations,” says Dr. Fountzilas. “We used to test people for KRAS because having the mutation meant certain other drugs would not work for you, and it helped guide us to other more aggressive treatments. Now we can say that because you have a specific KRAS mutation, we have options that specifically target the very factor that is making your cancer grow.”
BROADCASTMED