Potential drugs hold promise for targeting a range of KRAS-driven cancers in the lab

SCRATCH was one of the first cancer genes ever discovered, but for a long time the cancer-causing KRAS protein was considered “uncurable” with targeted therapy. That began to change in May 2021, when the Food and Drug Administration approved sotorasib (Lumakras®) for lung cancer caused by a certain SCRATCH called mutation SCRATCH G12C. Sotorasib’s groundbreaking approval was based on years of lab research and clinical trials, much of that work led by physician-scientist Piro Lito, MD, PhD, and other Memorial Sloan Kettering Cancer Center (MSK) investigators.

But G12C is just one of many mutations in it SCRATCH (pronounced “kay-rass”) known to cause cancer, and lung cancer is just one of many cancers associated with these mutations. In a paper published May 31, 2023, in Nature, researchers led by Dr. Lito exciting results for a new molecule that can block many more mutated forms of the KRAS protein. In the lab, the compound was effective at blocking the growth of multiple cancer cell lines, including lung cancer, colon cancer and pancreatic cancer. It was also effective in mouse models of lung and colon cancer caused by KRAS.

“KRAS is the most activated protein in cancer,” says Dr. Lito, a thoracic oncologist who also directs a lab in MSK’s Human Oncology and Pathogenesis Program. “Although they are important, the drugs we have developed so far only help a limited number of people. The inhibitor described in this paper has important therapeutic implications for the treatment of patients with more cancer types and more SCRATCH mutations.”

Compound inactivates a series of KRAS mutant proteins

KRAS-driven cancers have long been considered incurable Unpleasant the unusual shape of the protein. Because KRAS is smooth and round, it was difficult to find a targeted drug that could pin down and block the protein’s activity. Ten years ago, researchers discovered that the G12C version of the protein had a small pouch that opened and closed depending on whether the protein was active. Within a few years, drugs were developed that fit into that bag and turn off the protein. But those drugs were ineffective against other forms of KRAS mutations that were out of pocket.

BI-2865, the inhibitor analyzed in this study, binds to the KRAS protein in a different way, taking advantage of properties of the protein that were previously unknown.

“We were surprised that BI-2865 was able to inactivate the most common cancer-causing KRAS mutants,” said Dongsung Kim, PhD, a research associate of Dr. Lito and the first author of the study. “These mutants were thought to be locked in an active state of cancer, but if that were true, this drug wouldn’t work at all. This research opens a new direction in our understanding of how these mutations cause cancer.” In fact, lab studies showed that the new inhibitor was able to block 15 other versions of KRAS in addition to the G12C mutation.

Moving New KRAS Inhibitors to Clinical Trials

BI-2865 was developed by researchers at the pharmaceutical company Boehringer Ingelheim, who participated in and co-supervised this study. It’s a prototype that needs to be refined before testing in patients, but the company is working on new molecules optimized for clinical development. Dr. Lito plans to continue working with company researchers and hopes to have drugs ready for testing in clinical trials within a year.

“The ability to attack multiple KRAS mutants with a single molecule provides more definitive evidence that KRAS is finally drugable after more than 40 years of research,” said Dr. Lito. “This work has the potential to benefit a large number of people with cancer, including lung, colorectal and pancreatic cancer.”