Medical genetics

mutated form earning its reputation as “undruggable.” Yet; the hunt for an Achilles’ heel continues, as cancers driven by KRAS mutations are both common and deadly. Because Scientists from Sanford Burnham Prebys and PHusis Therapeutics have shown that a compound called PHT-7.3 shrinks KRAS-driven tumors in mice. Therefore In contrast to directly targeting mutant KRAS; the potential drug candidate targets the protein’s partner in crime: the cellular scaffold to which mutated KRAS attaches.

Potential drug candidate

The study is publish in Cancer Research. “Researchers have successfully developed personalize therapies for other mutations known to drive cancer growth; such as EGFR and BRAF. However; KRAS has remained infamously elusive,” says Garth Powis, D.Phil, senior author of the paper; director of Sanford Burnham Prebys’ NCI-designated Cancer Center and scientific co-founder and adviser to PHusis Therapeutics.

“Our study identifies a promising compound that has the potential to become a much-needed treatment for KRAS-driven cancers; an important advance for the millions of people around the world who are fighting this deadly cancer type.” KRAS is a protein that regulates cell growth. Because If it becomes mutated; it can get stuck in the “always on” conformation; leading to the uncontrolled cellular growth that causes cancer.

Regulates cell growth

The mutation occurs in approximately 25% of all human cancers, including more than 90% of pancreatic cancers, 35 to 45 percent of colorectal cancers and approximately 25% of lung cancers. There is currently no effective treatment for KRAS-positive cancers. “Mutated KRAS is firing all the time similar to speedily typed Morse code versus a calm; intermittent key tap,” explains Powis.

“This out-of-control signaling drives tumor growth and is particularly insidious because it overpowers targeted therapies that may otherwise have been able to treat the cancer.” In the study; the scientists focused on mutant KRAS’ accomplice, a protein called Cnksr1 (connector enhancer of kinase suppressor of Ras 1). Mutant KRAS floats to the cellular membrane and attaches to this scaffold to become active.

Overpowers targeted therapies

After demonstrating that inhibiting Cnksr1 halts the growth of lung and colon cancer cells, the researchers conducted molecular modeling and structural modifications to identify PHT-7.3. This small molecule probe the starting point for further drug development shrank KRAS-driven tumors in a mouse model of non-small-cell lung cancer. Importantly, the compound did not affect the function of healthy KRAS indicating that potential side effects may be limited.