Cell-penetrating antibodies could crack 'undruggable' cancer mutation

RAS mutations have long been an attractive target in cancer treatment, but scientists have struggled to find a drug that safely combats their effects. A South Korean team has developed a way to block RAS activity in tumor cells, thus promoting anti-tumor activity.

RAS mutations, which show up in about 30% of all cancers, activate RAS proteins. Tumors that contain these aberrations tend to be aggressive and resist treatments. And while scientists have worked on this target for decades, it is still thought of as “undruggable.”

Scientists at Ajou University and Orum Therapeutics devised a monoclonal antibody, RT11-i, which targets the RAS protein in cells. After it penetrates cells, it selectively binds to activated RAS, stopping it from interacting with effector proteins and setting off a cascade of tumor-promoting signaling.

In mice with tumors containing a RAS mutation, the treatment had “measurable antitumor activity,” according to a statement. The team also administered RT11-i alongside the EGFR inhibitor cetumixab to mice with treatment-resistant colorectal cancer. The combo unlocked the resistance, suggesting a possible treatment for patients with advanced colon cancer and RAS mutations, said principal investigator and Orum cofounder Yong Sung Kim.

"As an anti-cancer therapy, our cell penetrating antibodies are easy to produce, allow for systemic administration that is well tolerated, and have desirable pharmacological properties," said Sung Joo Lee, Ph.D., Co-founder and CEO of Orum Therapeutics. "We believe this could be a very important first-in-class therapeutic for hard-to-treat pancreatic, colon and non-small cell lung cancers." The work is published in Nature Communications.

Another way to target activated RAS is to use a synthetic binding protein, also called a monobody. A team from the University of Illinois at Chicago found that its NS1 monobody binds to a spot on the RAS protein molecule, which stops it from joining with an identical molecule to form a pair. This blocks the oncogenic activity of two out of three RAS proteins.

Successfully blocking RAS activity could be important for often deadly pancreatic cancers, 95% of which have RAS mutations, as well as for colorectal cancer (45%), lung cancer (35%) and melanoma, the deadliest of the skin cancers.