Third Generation Inhibitors Show Efficacy in Kidney, Breast Cancers

A third generation mTOR inhibitor called Rapalink was found to bind to the mTOR molecule in 2 places, combating growth in drug-resistant tumors.

There are several anti-cancer drugs on the market that attempt to halt tumor growth by blocking mTOR. One of the oldest drugs, rapamycin, and related molecules called rapalogs, build up resistance after months or years of treatment, despite early success in the treatment of kidney and breast cancers.

Since resistance to second-generation mTOR inhibitors is likely, researchers sought to address the problem before the development is able to occur. In a study published in Nature, researchers looked to explore the use of third generation mTOR inhibitors before patients built up resistance.

At the beginning of the study, drug-resistant cells were examined to identify the specific changes that allowed these cells to thrive. Next, genetic databases that catalogued tumors from cancer patients was searched for mutations.

The study revealed the mutations that caused the lab-grown cancer cells to become resistant to ADZ8055 had a presence in the tumors even before treatment.

“That really was a shock, because usually those are drug-induced mutations,” said study investigator Kevan Shokat.

Changes found in approximately 10% of renal cell tumors were found to aid tumor growth with or without ADZ8055. Researchers said the tumors that carried the mutations would never respond to the second generation mTOR inhibitor.

“Immediately, the project changed from 'down the road patients are going to have these mutations, so we're going to need a drug' to 'wow, patients already have these mutations, and they are de novo resistant to the drug we have in the clinic,’” Shokat said.

For third generation mTOR inhibitors, researchers were inspired by the immune system to create an inhibitor that worked differently than its predecessors. The Y-shaped structure of antibodies contains 2 antigen-binding tips, allowing them to bind rapidly to changing targets.

These 2 binding sites cause the antibodies to develop a strong affinity for their targets. Researchers wanted to mimic this strategy by creating an inhibitor that could bind to mTOR in 2 places.

During the study, researchers linked a first generation mTOR inhibitor, which binds to one part of the molecule, with a second generation inhibitor that targets a separate area nearby.

Rapalink was able to grab onto mTOR in both areas, allowing them to bind more effectively than the earlier generation inhibitors. Furthermore, Rapalink was able to bind to mTOR even if it contained mutations that normally stop other inhibitors from binding.

According to researchers, it isn’t imperative for both mTOR binding sites to perfectly match the drug. Once one side of the inhibitor binds to its target, the other end side follows because of its close proximity to its own pocket.

The tethered binding sites means that the second side of the inhibitor will most likely bind to the target as well. The findings revealed that Rapalink was able to turn off mTOR in cancer cells, even if the cells become resistant to earlier generation inhibitors.

Further research conducted by the study authors revealed that Rapalink was able to inhibit tumor growth in animal models, reducing the size of the first or second generation drug-resistant tumors. Additionally, researchers will continue to evaluate the inhibitors to determine its potential as a cancer therapy drug.