University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Hybrid Cancer Drug Could Be Resistance-Resistant

Conjoined Compounds Deal Double Blow To Resistant Cancers in Cells and Mice

By Nicholas Weiler | | May 18, 2016

Hybrid Cancer Drug Could Be Resistance-Resistant

Kevan M. Shokat, PhD

A team of cancer researchers led by scientists at UC San Francisco and Memorial Sloan Kettering Cancer Center demonstrated in human cells and mouse models that a first-of-its-kind hybrid drug can outsmart drug-resistant cancers.

The new drug physically yokes together two existing drugs against a common cancer pathway into a single molecule, generating a double-blow that blocked the resistance cancer cells otherwise develop to either drug on its own.

The researchers, who published their finding online on May 18, 2016 in the journal Nature, hope that their new approach will lead to a whole class of new therapies that keep cancer at bay much longer and improve patient survival.

“Every time we find a new drug target against cancer, we go through one, two, three generations of drugs as the cancer keeps evolving resistance,” said study co-senior author Kevan Shokat, PhD, professor and vice-chair of the department of Cellular and Molecular Pharmacology at UCSF. “What we really wanted to do was get out ahead of this cycle of resistance.”

Researchers Unravel Mechanisms of Drug Resistance in Common Cancer Pathway

Precision medicine approaches to cancer, which involve targeting the specific mutations driving an individual patient’s disease, run the risk of promoting treatment-resistant tumors by killing off drug-sensitive cancer cells and allowing a minority of mutant, drug-resistant cells to thrive in their place.

Mutations driving over-activation of the protein mTOR — a key molecule regulating cellular growth, division, proliferation, and other important functions — are common factors of many different cancers, making mTOR a key target for anti-tumor therapies. The drug rapamycin and similar therapies that interfere with mTOR’s function (such as everolimus, or Afinitor, and temsirolimus, also known as Torisel) have been approved for the treatment of a several cancers, including kidney cancer, pancreatic neuroendocrine tumors, and advanced breast cancer.

Unfortunately, tumors treated with these first-generation mTOR inhibitors often evolve resistance to these drugs. Second-generation mTOR inhibitors, which work by jamming mTOR’s ATP site – it’s molecular “engine” — are currently in clinical trials, but tumors will assuredly evolve resistance to these drugs too in time, researchers say.

Members of Shokat’s laboratory, in collaboration with the researchers in the lab of co-senior author Neal Rosen, MD, PhD, the Enid A. Haupt Chair in Medical Oncology at Memorial Sloan Kettering Cancer Center, began to search for new approaches to attacking these cancers that might avoid the trap of resistance.

They started by treating human breast cancer cell lines with either first- or second-generation mTOR inhibitors to better understand how resistance to these drugs develops. They discovered that the two forms of resistance were quite different: Rapamycin resistance arises when mutations change the mTOR molecule’s shape, making it hard for rapamycin to bind to its normal site. Resistance to the second-generation mTOR inhibitors, on the other hand, evolves when mutations send mTOR’s ATP site into over-drive, requiring potentially toxic levels of second-generation drugs to bring it under control.

When the researchers looked for these ATP-site mutations in cancer genome databases, they found that many patients are already likely resistant to the second-generation drugs.

Hybrid Drug Prevents Resistance in Human Cells, Mouse Models

The idea for the new hybrid drug came as the researchers examined where resistance to the two drug classes arises within the 3D structure of the mTOR molecule, and realized that the drugs’ binding sites were close enough together that a combined molecule could hit both of the protein’s weak spots at once.

The researchers designed a chemically linked hybrid of the two types of drug, creating a new drug they call RapaLink, and demonstrated in cultured human breast cancer cells that each half of the new drug could counteract any resistance the cancer cells might develop to the other half.  Specifically, the carefully calibrated bridge between the two sides of the hybrid drug meant that if one side of RapaLink was able to bind to its specific site on the mTOR molecule, this would perfectly position the other side of RapaLink in front of its own binding site, making it much harder for mTOR mutations to shake the drug off.

“The effective concentration is sky-high,” Shokat said. “It’s like how you’re more stable on skis than on a snowboard. Having that second binding is very helpful for stability.”