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Compound Shrinks KRAS-Driven Tumors by Targeting Partner

Mary Caffrey
Researchers say by targeting a protein that assists KRAS mutations, they have overcome the challeges of resistance to treatment in a mouse model.
Amid the many leaps in cancer research are frustrations, and among them are KRAS-driven tumors. Where researchers have developed drugs that successfully target other mutations, KRAS mutations remain stubbornly resistant.

Yet the search for way to block the effects of KRAS mutations goes on, because they appear in 25% of all cancers. And now researchers at Sanford Burnham Prebys Medical Discovery Institute, working with PHusis Therapeutics, have published results on a compound called PHT-7.3, which they say shrinks tumors not by hitting the KRAS mutation directly, but by taking out the cellular structure that supports it.

Results appeared in Cancer Research, the official journal of the American Association of Cancer Research.

“Researchers have successfully developed personalized therapies for other mutations known to drive cancer growth, such as EGFR and BRAF. However, KRAS has remained famously elusive,” Garth Powis, DPhil, senior author and director of Sanford Burnham Prebys’ NCI-designated cancer center, said in a statement. “Our study identifies a promising compound that has the potential to become a much-needed treatment for KRAS-driven cancers.”

The K-Ras protein regulates cell growth, and when it is mutated cells grow uncontrollably. KRAS mutations are seen in 90% of pancreatic cancers, which has a 5-year survival rate of 9%. A colorectal cancer patient with a KRAS mutation, which accounts for 35% to 45% of the cases, is unlikely to respond to cetuximab or panitumumab.

“Mutated KRAS is firing all the time,” said Powis, who is also a co-founder of PHusis Therapeutics. “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.”

Researchers focused on a separate protein called Cnksr1, or connecter enhancer of kinase suppressor of Ras 1. To become active, mutant KRAS must attach to this cellular membrane of this protein, like a scaffold. First, the researchers showed that inhibiting Cnksr1 halted the growth of lung and colon cancer cells. Then, they conducted molecular modeling to identify PH-7.3, which will be the starting point for future drug development. The compound shrank KRAS-driven tumors of non–small-cell lung cancer in mice, but the treatment did not affect healthy KRAS. The researchers say this may suggest that side effects will be limited.

Reference

Indarte M, Puentes R, Maruggi M, et al. An inhibitor of the pleckstrin homology domain of CNK1 selectively blocks the growth of mutant KRAS cells and tumors [published online April 30, 2019]. Cancer Res. 2019; DOI: 10.1158/0008-5472.CAN-18-2372.

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