Drug-Resistant Cancer May Be Combatted With New Generation mTOR Inhibitors

A potential cancer therapy with a unique strategy to block the mechanistic target of rapamycin (mTOR) molecule has been designed. mTOR helps to drive the growth of many tumors. In animal experiments, Rapalink, this new mTOR-inhibiting compound, the size of tumors resistant to earlier-generation mTOR inhibitors were reduced.1

mTOR is a key part of a growth-regulating network often disrupted in cancer cells. Rapamycin is the oldest of the drugs that block mTOR, and it has had success in treating a few types of cancer, including kidney and breast cancers. Clinical trials evaluating second-generation mTOR inhibitors, rapalogs, which are more potent than the first-generation molecules, are currently ongoing.

Resistance to rapalogs can develop after months or years of effective treatment. Resistance to second-generation mTOR inhibitors is also expected. However, understanding the changes that make cancer cells resistant to a drug can help scientists develop a next-generation therapy.

To get ahead of the resistance problem, this team of researchers began considering third-generation mTOR inhibitors without waiting for resistance to the latest therapies to develop. The researchers were led by Kevan Shokat, PhD, at the University of California San Francisco, and Neal Rosen, MD, PhD, at Memorial Sloan Kettering Cancer Center in New York City.

To anticipate how resistance might arise, Rosen's team exposed breast cancer-derived cells they grew in the laboratory to either rapamycin or to a second-generation mTOR inhibitor, ADZ8055, for 3 months. Most of the cells died, but as expected, some found a way to survive and multiply.

The researchers examined those drug-resistant cells to identify the specific changes that had allowed them to thrive, reasoning that the same changes might arise in patients who received the drugs. Then Rosen's team searched for the mutations in genetic databases that catalogued tumors from cancer patients.

The researchers were surprised to discover that the mutations that had made their laboratory-grown cells resistant to ADZ8055 were present in some patients' tumors even before treatment.

"That really was a shock, because usually those are drug-induced mutations," Shokat explained. The changes, present in approximately 10% of renal cell tumors (the most common type of kidney cancer), boosted mTOR activity, which meant they aided tumor growth with or without ADZ8055. Tumors carrying these mutations would never respond to second-generation mTOR inhibitors.

"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,'" said Shokat.

The scientists set to work designing an mTOR inhibitor that worked differently than its predecessors. They mimicked antibodies by creating an inhibitor that binds mTOR in 2 places. The new mTOR inhibitor, Rapalink, links a first-generation mTOR inhibitor, which binds to one part of the molecule, to a second-generation inhibitor, which targets a separate pocket nearby.

Initial tests of Rapalink have been promising. The scientists have licensed Rapalink to Kura Oncology, which will continue to evaluate its potential as a cancer therapy. Shokat and Rosen are scientific advisors to Kura Oncology.

Reference

1. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor [published online May 18, 2016]. Nature. doi:10.1038/nature17963.

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