New Hybrid cancer drug might be resistance-resistant

New Hybrid cancer drug might be resistance-resistant

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.

“Every time we find a new drug target against cancer, we go through one, two, three generations of drugs as cancer keeps evolving resistance,” said study co-senior author Kevan Shokat, Ph.D., professor and vice-chair of the department of cellular and molecular pharmacology at UCSF. “What we 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 involves 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.

The drug rapamycin and similar therapies that interfere with mTOR’s function have been approved for the treatment of several cancers, including kidney cancer, pancreatic neuroendocrine tumors, and advanced breast cancer.

Members of Shokat’s laboratory, in collaboration with the researchers in the lab of co-senior author Neal Rosen, M.D., Ph.D., 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.

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.

The 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 3-D 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 were able to bind to its specific site on the mTOR molecule, this would perfectly position the other side of RapaLink in front of its binding site, making it much harder for mTOR mutations to shake the drug off.

As a result, even against cancer cells resistant to both types of drugs on their own, the hybrid drug continued to be effective.

The researchers also tested RapaLink in mice grafted with human breast cancers with genetic resistance to either first or second-generation mTOR inhibitors and found that RapaLink could get around the cancers’ drug resistance.

Finally, further experiments in cell lines showed that while cells treated with first- or second-generation mTOR inhibitors rapidly evolved resistance within three months, cells treated with RapaLink evolved no resistance to the drug for the 9-month period of the study.

“It would be foolhardy to say that we can completely stop cancer from evolving resistance,” Shokat said.

“But we do think this drug has the potential to make resistance develop much less frequently, and take much longer to develop, which we hope will give patients a lot more time to recover and fight off cancer.”

Shokat and colleagues have patented the RapaLink drug and have licensed it to Kura Oncology to bring the drug to clinical trials.

Shokat believes the approach taken to block resistance to mTOR inhibitors could be applied more generally to other cancer pathways.