Combination inhibitor fights drug-resistant cancer

Cancer can be a wily foe. A recent article in New York Times Magazine illustrates the extent of cancer’s craftiness, telling the story of a woman whose thyroid cancer developed resistance to the common chemotherapy drugs everolimus and temsirolimus. These drugs are supposed to work by inhibiting an enzyme, mTOR, that helps cells—particularly cancer cells—grow. But the woman’s cancer had mutated, rendering the drugs ineffective.

The May 15 article “covers the type of cancer patient and emerging resistance that stimulated our new work on mTOR inhibitors,” says Kevan Shokat of the University of California, San Francisco. Shokat, Neal Rosen of Memorial Sloan Kettering Cancer Center, and coworkers report a drug candidate that’s more potent than approved mTOR inhibitors such as everolimus and also less likely to be defeated by drug resistance.

They accomplished the feat by combining two types of mTOR inhibitors, which hit separate target sites on the enzyme, into a bivalent agent that hits both simultaneously (Nature 2016, DOI: 10.1038/nature17963). Shokat has patented the new drug design for development by Kura Oncology, a company he helped found.

“This is a very important paper with huge potential for cancer therapy,” says Nahum Sonenberg, an mTOR and cancer specialist at McGill University.

mTOR controls a cell-signaling pathway that is commonly activated in many human cancers. Researchers developed everolimus and temsirolimus to inhibit that pathway. The drugs, analogs of the bacterial natural product rapamycin, target a rapamycin-binding site in mTOR.

A more recently developed “second generation” of mTOR inhibitors work by hitting another mTOR site, where the enzyme typically binds adenosine triphosphate (ATP). Several second-generation mTOR inhibitors are currently in clinical trials.

Unfortunately, tumor cells have proven talented at developing mutations that make both first- and second-generation mTOR inhibitors ineffective.

Shokat, Rosen, and coworkers determined that the two binding sites in mTOR are 15 Å away from one another. So they took rapamycin and a second-generation inhibitor called MLN0128, which binds mTOR’s ATP site, and combined them with a polyethylene glycol-based linker that spans that gap between the two sites. This combined third-generation agent, dubbed RapaLink-1, binds both sites simultaneously and potently inhibits the growth of nonresistant and drug-resistant cancers in tumor cell cultures and in mice.

Kinase inhibitor expert Nathanael Gray of Dana-Farber Cancer Institute says he wouldn’t have predicted that such a large molecule would be effective. But he says that two characteristics of RapaLink-1—its bivalency and its tendency to concentrate in red blood cells that deliver it to cancers—likely account for its high potency. He notes that cancers are less likely to find a way to sidestep its activity because they would need to mutate twice instead of just once to mount resistance.