Triple-negative breast cancer may adopt a reversible chemotherapy-resistant state


breast cancer

Micrograph showing a lymph node invaded by ductal carcinoma of the breast, with tumor extension beyond the lymph node. Credit: Nephron / Wikipedia

Researchers at the University of Texas MD Anderson Cancer Center have found that triple-negative breast cancer cells (TNBC) may develop resistance to front-line or neoadjuvant chemotherapy, not acquiring permanent adaptations but transiently rotate in molecular pathways that protect the cells.

The study, published today in Translational medicine of sciencealso identifies a vulnerability that may provide a new treatment option for rugged TNBC. Among these activated pathways is a metabolic process, known as oxidative phosphorylation, which may be the target of a small molecule drug developed by MD Anderson's Therapeutics Discovery division.

"Modern chemotherapy is highly effective for almost half of patients with triple negative breast cancer," said corresponding author Helen Piwnica-Worms, Ph.D., professor of Experimental Radiation Oncology. "However, the remaining half of women will not respond completely to neoadjuvant chemotherapy, and there are currently no approved treatments to improve outcomes. Understanding how tumor cells become resistant will allow us to identify new targets to better treat resistant diseases."

According to the American Cancer Society, it is estimated that 268,000 women will be diagnosed with breast cancer this year, of which 15 to 20 percent will have TNBC. The standard treatment for patients with TNBC is neoadjuvant chemotherapy followed by surgery for tumor removal. For women with tumors that do not respond fully to chemotherapy, there is a much greater risk of recurrence and death of the disease, said Piwnica-Worms.

To study how TNBC cells become resistant to treatment, the researchers created models of mice, known as TNBC patient-derived xenografts (PDXs) using tumor samples from patients enrolled in the ARTEMIS clinical trial, led by MD Anderson. .

Patients enrolled in ARTEMIS perform tumor biopsies before and after neoadjuvant chemotherapy, which allows researchers to study why some tumors are resistant and to find more effective strategies to bring more patients to cure. The work is part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific breakthroughs in clinical advances that save lives of patients.

The Piwnica-Worms team identified several PDX models that responded to chemotherapy initially, but eventually developed resistance and resumed tumor growth. If the treatment was paused, however, the residual tumors once again became sensitive to chemotherapy, indicating that the resistance was temporary.

Under the microscope, the tumors showed distinct changes during treatment, but the tumors reappeared similarly to those that occurred before treatment. In addition, analysis of individual tumor cells showed that the heterogeneity of cells in a given tumor was maintained after treatment, suggesting that chemotherapy did not select a small subset of resistant cells.

The characterization of gene expression alterations revealed a set of activated pathways as part of the resistant state, which were switched off when chemotherapy was discontinued. The researchers confirmed that many of these molecular changes were mirrored in biopsies of ARTEMIS patients.

In the hope of finding new treatment targets for resistant TNBC, the researchers found that these cells have become dependent on oxidative phosphorylation for energy production. This path is the target of IACS-10759, the first small molecule discovered and developed by MD Anderson's Therapeutics Discovery division.

In treating PDX mice with IACS-10759 after chemotherapy, the researchers observed a synergistic effect, suggesting that sequential chemotherapy and IACS-10759 treatment could prolong the duration of treatment response. IACS-10579 is now in clinical trials for a variety of hematologic and solid cancer types.

"Our study provides a compelling reason to define additional properties that allow triple-negative breast cancers to survive chemotherapy, so that combined therapies can be developed to eradicate this disease," says Piwnica-Worms. "A long-term goal is to avoid the use of chemotherapy in patients with resistant disease and instead employ targeted therapies to avoid unnecessary treatments and severe side effects."

Aggressive breast cancer already has resistant tumor cells before chemotherapy

More information:
G.V. Echeverria et al., "Resistance to neoadjuvant chemotherapy in triple negative breast cancer mediated by a reversible drug tolerant state" Translational medicine of science (2019)… scitranslmed.aav0936

Provided by
University of Texas Cancer Center M. D. Anderson

Triple-negative breast cancers may adopt a reversible chemotherapy-resistant state (2019, April 17)
recovered April 17, 2019

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