A combination therapy may counter the resistance to human epidermal growth factor receptor 2 inhibitor neratinib in patients with breast, ovarian, lung, or other cancers.
Researchers at the University of Texas Simmons Cancer Center have discovered a 2-drug combination that halts the growth of cancer cells carrying human epidermal growth factor receptor 2 (HER2) mutations, according to a study published in Cancer Cell.
Previous research has found that after an initial response, patients with cancers with HER2 mutations eventually develop resistance to the HER2 inhibitor neratinib (Nerlynx, Puma Biotechnology, Inc), a promising new cancer drug currently in clinical trials.
Everolimus (Afinitor, Novartis) counters that resistance and blocks the cancer. This interaction provides the basis for a novel drug combination against cancers with HER2 mutations, according to the study authors.
Researchers evaluated data from a molecularly guided trial in which patients with tumors with HER2 mutations were treated with neratinib. The cancer was then sequenced as the disease progressed during participants’ treatment. Based on this analysis, researchers discovered in the laboratory that an effective way to offset eventual resistance to neratinib is with everolimus, a target of rapamycin complex 1 (TORC1) inhibitor commonly used to treat other types of breast cancer.
HER2 mutations have long been identified as a key driver in various cancers. The study authors analyzed a signaling network driven by TORC1, the pathway through which HER2-mutant cancers become neratinib-resistant, according to a press release.
“This finding may give clinicians an effective response to neratinib resistance. That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations,” said corresponding author Carlos L. Arteaga, MD, director of the Simmons Cancer Center at UT Southwestern, in the press release.
In addition to study tumor sequencing data from patients with HER2-mutant cancer in clinical trials for neratinib, the researchers studied neratinib-resistant cells and tumors that continue to live and grow in the laboratory.
Cancer sequencing before and during the clinical trial showed that certain patients previously had a mutation that could activate the TORC1 pathway. Other patients develop it eventually but could benefit from everolimus, which would allow the patient to continue benefitting from neratinib’s inhibition of HER2, according to the study.
Researchers uncover two-drug combo that halts the growth of cancer cells [news release]. Dallas, Texas; January 23, 2020. https://www.utsouthwestern.edu/newsroom/articles/year-2020/two-drug-combo-cancer.html. Accessed January 28, 2020.