Triple negative breast cancers can adopt a reversible state resistant to chemotherapy

Researchers at the MD Anderson Cancer Center at the University of Texas have found that triple negative bad cancer (TNBC) cells can develop resistance to first-line or neoadjuvant chemotherapy, not by acquiring permanent adaptations, but by turning transiently the molecular pathways protecting the cells.

The study, published today in Translational medicine science, also identifies a vulnerability that could provide a new treatment option for TNBC resistant. Among the activated pathways is a metabolic process, called oxidative phosphorylation, that can be targeted by a small molecule drug developed by MD Anderson's Therapeutics Discovery division.

"Modern chemotherapy is very effective for nearly half of patients with triple negative bad cancer," said Helen Piwnica-Worms, Ph.D.'s corresponding author and professor of Experimental Radiation Oncology. "However, half of the remaining women will not fully respond to neoadjuvant chemotherapy and there is currently no approved treatment to improve the results.Understanding how tumor cells become resistant will enable us to identify new targets for better treat resistant diseases. "

According to the American Cancer Society, approximately 268,000 women will be diagnosed with bad cancer this year, of which 15 to 20% will have TNBC. The standard treatment in patients with TNBC is neoadjuvant chemotherapy followed by surgery to remove the tumor. For women whose tumors do not fully respond to chemotherapy, the risk of recurrence and death is much higher, said Piwnica-Worms.

To investigate how TNBC cells become resistant to treatment, the researchers created mouse models, known as patient-derived xenografts (PDX), using tumor samples from patients enrolled in the trial. ARTEMIS Clinic, led by MD Anderson, Breast Cancer Moon Shot. .

Patients enrolled in ARTEMIS undergo tumor biopsies before and after neoadjuvant chemotherapy treatment, which allows researchers to investigate why some tumors are resistant and to discover more effective strategies for providing treatment to more patients. The work is part of MD Anderson's Moon Shots program, a collaborative effort designed to accelerate the development of breakthrough scientific breakthroughs that save the lives of patients.

The Piwnica-Worms team identified several models of PDX that initially reacted to chemotherapy but eventually developed resistance and resumption of tumor growth. However, if the treatment was on hold, the residual tumors became sensitive to chemotherapy, indicating that the resistance was temporary.

Under the microscope, the tumors showed distinct changes during treatment, but the tumors that regenerated appeared as before. In addition, an badysis of individual tumor cells showed that the heterogeneity of the cells of a given tumor was maintained after treatment, suggesting that chemotherapy did not select a small subset of resistant cells.

The characterization of gene expression modifications revealed a set of pathways activated as part of the resistance state, which were deactivated at the time of stopping chemotherapy. The researchers confirmed that many of these molecular changes were reflected in biopsies performed on ARTEMIS patients.

Hoping to find new therapeutic targets for resistant TNBC, the researchers found that these cells became 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.

When treating PDX mice with IACS-10759 after chemotherapy treatment, the researchers observed a synergistic effect suggesting sequential treatment of chemotherapy and IACS-10759 could prolong the duration of the response to treatment. IACS-10579 is currently undergoing clinical trials involving various types of hematologic and solid cancers.

"Our study provides a compelling rationale for defining additional properties that allow triple-negative bad cancers to survive chemotherapy treatment, so that combined therapies can be developed to eradicate this disease," Piwnica-Worms explains. "A long-term goal is to avoid the use of chemotherapy in patients with resistant disease and to resort to targeted treatments to avoid unnecessary treatments and severe side effects."