UT Southwestern Simmons Cancer Center researchers have discovered a two-drug combination that halts the growth of cancer cells that carry HER2 mutations. Patients with cancers harboring HER2 mutations eventually develop resistance to a promising new cancer drug currently clinical trial.
Published in journal Cancer Cell, the researchers found that another drug, already on the market, counters that resistance and blocks the cancer, thereby providing the basis for a novel drug combination against cancers mutations in the HER2 gene.
The team led by Dhivya Sudhan, PhD, with the Harold C. Simmons Comprehensive Cancer Center and collaborators evaluated data from a molecularly guided trial where patients with tumors with HER2 mutations were treated with the HER2 inhibitor neratinib.
Patients’ cancers were sequenced as the disease progressed during treatment. While analyzing the study data, Sudhan discovered that an effective way to offset eventual resistance to neratinib is with everolimus, a TORC1 inhibitor commonly used to treat other types of breast cancer. Based on these findings, clinicians were lead to a potential way to counter the neratinib resistance. According to Carlos L. Arteaga, MD, Director of the Simmons Cancer Center and corresponding study author, “That could make a real difference for patients with breast, ovarian, lung and other cancers harboring HER2 mutations.
HER2 mutations have long been associated as an important element contributing to breast and other cancers. The Simmons Cancer Center authors focused on a signaling network driven by TORC1, which they demonstrated is the pathway through which HER2-mutant cancers become neratinib-resistant.
Hence the researchers not only studied tumor sequencing data from HER2-mutant cancer patients across the country who are in neratinib clinical trials, but also assessed neratinib-resistant cells and tumors that live and grow in laboratory tests environments.
They ultimately found that everolimus would allow the patient to continue benefitting from neratinib’s inhibition of HER2. The combination of neratinib and everolimus worked in cell lines, organoids established from patient-derived tumors, and in mice harboring.
What is Neratinib & Everolimus?
Neratinib is used as adjuvant therapy in patients with early-stage breast cancer in which HER2 is overexpressed after the person receiving treatment with trastuzumab. A clinical trial demonstrated that Neratinib and Temsirolimus in combination produced responses in 19% of patients ranging from 2 to 18+ months in patients with HER2-mutant lung cancers. A common toxicity, diarrhea, was well-managed with loperamide prophylaxis. Originally developed by Wyeth—which became Pfizer after an acquisition. After that, Puma Biotechnology licensed the intellectual property and now has the product rights.
Everolimus is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants and in the treatment of renal cell cancer and other tumors. A considerable amount of research has been accomplished with everolimus and other mTOR inhibitors as targeted therapy for use in other cancers.
Marketed under the trade name Zortress (USA) and Certican (Europe and other nations) in transplantation medicine, and as Afinitor (general tumors) and Votubia (tumors as a result of TSC) in oncology. The drug is also available from Biocon with the brand name Evertor.
The study was funded by the following organizations: Simmons Cancer Center, the Cancer Prevention & Research Institute of Texas, the National Cancer Institute Breast SPORE, the Vanderbilt-Ingram Cancer Center, Susan G. Komen Breast Cancer Foundation, the Breast Cancer Research Foundation, and the Susan G. Komen Postdoctoral Fellowship. Moreover, UT Southwestern Tissue Resource, supported by the National Cancer Institute, provided critical support.
About UT Southwestern
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.
Dhivya Sudhan, PhD, Simmons Cancer Center, UT Southwestern
Carlos L. Arteaga, MD Director of the Simmons Cancer Center, UT Southwestern
Note dozens of authors were involved, and their names can be viewed via the source link below.