Researchers ID Promising 2-Drug Combo for Resistant Breast Cancer

Breast cancer

Researchers are constantly finding drug combinations that help fight drug-resistant cancers. Researchers at the UT Southwestern Medical Center appeared to have found a new one using already approved drugs.

The investigators were studying data from a “molecularly guided trial” in which breast cancer patients with HER2 mutations received neratinib (Puma Biotechnology’s Nerlynx), which is a HER2 inhibitor. If the disease progressed despite treatment, the researchers sequenced the DNA of the tumors. They found in the laboratory that an effective approach to battling eventual resistance to neratinib was another drug, everolimus (Novartis’ Afinitor). Everolimus is a TORC1 inhibitor often used to treat other forms of breast cancer.

“This finding may give clinicians an effective response to neratinib resistance,” said Carlos L. Arteaga, director of the Simmons Cancer Center at UT Southwestern and corresponding author of the research. “That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations.”

HER2 mutations are known to drive breast cancer and other cancers. The researchers focused on a signaling network driven by TORC1. The network is the pathway where HER2-mutant cancers develop resistance to neratinib.

“We consistently noted activation of TORC1 signaling as a mechanism of resistance to neratinib across different types of HER2-mutant cancers,” said Dhivya Sudhan, a postdoctoral research fellow at the Harold C. Simmons Comprehensive Cancer Center. “Different cancer types used different strategies to escape neratinib, but they all converged on TORC1 signaling.”

They evaluated the research in data from clinical trials across the country as well as in neratinib-resistant cells and tumors grown in the laboratory. Some patients, they found, already had a mutation that could possibly activate the TORC1 pathway. Others developed it. Both groups could potentially benefit from everolimus, which would extend the patient’s ability to respond to neratinib.

At this time the combination worked in cell lines, in organoids developed from patient-derived tumors, and in mice with the HER2 mutant tumors. They hope to begin testing the two-drug combo in human clinical trials.

The research was published in the journal Cancer Cell.

Earlier this week, researchers at the Broad Institute of MIT and Harvard tested about 4,518 drugs on 578 human cancer cell lines. They discovered that almost 50 had previously unrecognized anti-cancer properties. The drugs ranged from treatments for diabetes, inflammation, alcoholism and arthritis in dogs.

“We thought we’d be lucky if we found even a single compound with anti-cancer properties, but we were surprised to find so many,” said Todd Golub, chief scientific officer and director of the Cancer Program at the Broad.

The research leveraged the Broad’s Drug Repurposing Hub. This Hub is made up of more than 6,000 existing drugs and molecules the U.S. Food and Drug Administration (FDA) has either already approved or have been shown to be safe in clinical trials. At the time the group conducted their study, there were 4,518 compounds in the Hub.

“Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms,” Steven Corsello said. Corsello is an oncologist at Dana-Farber Cancer Institute, founder of the Drug Repurposing Hub, member of the Golub lab and first author of the study, which was published in the journal Nature Cancer.

For example, some of the drugs activated a protein or stabilized a protein-protein interaction. Almost a dozen of the non-cancer drugs killed cancer cells expressing the PDE3A protein by stabilizing the PDE3A and SLFN12 protein interaction. This was an unknown mechanism.

Many of the drugs killed cancer cells by interacting with a previously unrecognized molecular target. One example is the drug tepoxalin, used to treat osteoarthritis in dogs. But the drug killed cancer cells by interacting with an unknown target in cancer cells that overexpress the MDR1 protein, which is linked to resistance to chemotherapy drugs.

The researchers were further able evaluate the cell line’s genomic features and predict which drugs could kill each cell line. Those genomic features included mutations and methylations levels, which were available in the CCLE database.

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