Takeshi Shimamura, an associate professor of surgery in the College of Medicine, sees cancer as a many-headed monster: adaptive, relentless and difficult to eradicate. Thwarting its progress is his Herculean research task.
“Cancer is clever. It knows how to overcome drugs, almost as if it has a mind of its own. It evolves and finds alternate pathways when its survival is threatened. That’s why I study drug resistance — to understand how it works and, ultimately, to outsmart it,” said Shimamura, who is also affiliated with the University of Illinois Cancer Center.
Shimamura studies how some cancers can become resistant to treatment and hinder patients’ recovery. Lately, he’s turned his attention toward a stubborn form of lung cancer that learns to resist some FDA-approved drugs. His latest study in the journal Cancer Letters introduces a drug designed to block two key proteins that help cancer survive and spread, even after other treatments stop working. The new molecule, RNK07421, binds to two proteins that work together to spread cancerous cells.
The first protein, KRASG12C, is a mutated version of the KRAS protein. Particularly prevalent in lung, colon and pancreatic cancer, this specific mutation helps cancer cells flourish and thrive, making tumors more aggressive and challenging to control.
“For a long time, we did not have a drug to target this mutation because its shape gave us no clear place for a drug to attach and block its activity,” Shimamura said.
“The KRASG12C mutation was known as ‘undruggable,’” he said. “It is only recent that started to change with the arrival of FDA-approved drugs. While these new drugs can work at first, many cancers figure out how to resist them over time, making the treatment less effective. This is where RNK07421 can be used.”
The new drug targets not only KRASG12C, but also HSP90, a “chaperone” protein that guards and guides cancer-causing proteins as they grow and multiply.
Results indicate that simultaneously inhibiting KRASG12C and HSP90 helps overcome drug resistance in KRASG12C-driven cancers. The molecule overcame drug resistance in lung cancer models and significantly shrunk drug-resistant tumors in both in-vivo and in-vitro models.
Shimamura said the two-in-one approach also can help in managing dosing and toxicity.
This work builds on Shimamura and colleague Ian Papautsky’s “tumor farm” study, which tested lung cancer drugs’ efficacy on hundreds of microscopic tumors from patients. Shimamura hopes to continue pursuing personalized and precision cancer treatments and eventually expand his study to colorectal and pancreatic cancer.
Shimamura said this research would not be possible without interdisciplinary collaboration across the university.
“This is the beauty of UIC, because we have so many experts on campus. It’s the beauty of translational research that the Cancer Center is trying to put together,” he said.
Additional UIC researchers are Ines Pulido, Qiyue Luan, Sara Pastor-Puente, Laura Gunder, Christian Ascoli, Khaled Abdelhady and Malek Massad.
The associated paper is titled “Chaperone directed heterobifunctional molecules circumvent KRASG12C inhibitor resistance.”
This research received funding from the U.S. Department of Defense’s Congressionally Directed Medical Research Program-Lung Cancer Research Program and the Mansueto Lung Cancer Research Fund. The experimental drug, RNK07421, was designed and synthesized by Ranok Therapeutics Co. Ltd.
