UT Southwestern Medical Center
Harold C. Simmons Comprehensive Cancer Center
Overcoming resistance to CDK4/6 inhibitors in estrogen receptor-positive metastatic breast cancer.
CDK4/6 inhibitors (CDK4/6i), such as palbociclib (Ibrance®) and abemaciclib (Verzenio®), revolutionized the treatment of metastatic estrogen receptor (ER)-positive breast cancer, and the combination of CDK4/6i with hormone therapy is now standard of care for these patients. But, while most initially respond, almost all patients eventually experience tumor progression due to therapeutic resistance. There is an urgent need to understand the molecular processes that drive resistance in order to improve survival. Dr. Hanker’s studies are dedicated to identifying genetic alterations that drive drug resistance and developing new therapeutic approaches to overcome resistance to CDK4/6i.
To find potential genes that contribute to resistance, Dr. Hanker’s team used ER-positive breast cancer cell lines that were genetically engineered to mutate frequently. They subjected these “hypermutable” cells to treatment with CDK4/6i and endocrine therapy, so that only the cells that acquired mutations causing drug resistance would survive. From these experiments, they identified several genes of interest that may initiate drug resistance. In parallel, they are also generating patient-derived “organoids” (PDOs) – samples of tumor biopsies that are grown in the lab for experimental purposes—that were taken from CDK4/6i-resistant tumors. These PDOs have been characterized at the protein, genomic and transcriptomic level to identify genes and resistance pathways of importance. They have also successfully grown a collection of PDOs that they used to perform an initial drug screen—testing 1,000 different drug compounds to see if any drug or combinations of drugs can help counter CDK4/6i resistance.
The team will continue to study potential resistance genes they found, confirming that they are responsible for CDK4/6i resistance. They continue to also test drugs that target these genes in laboratory models and the patient derived organoids. The team will continue testing these drugs to validate them for potential use as a combination strategy in ER-positive metastatic breast cancer. Dr. Hanker has been sharing the results of her research on mechanisms of resistance to CDK4/6i at scientific meetings and has a manuscript in preparation.
Ariella Hanker, PhD joined the faculty of UT Southwestern Medical Center in 2018. She received her BS in chemistry from the University of Virginia in 2004 and PhD in genetics and molecular biology from the University of North Carolina at Chapel Hill in 2009. Her graduate work in the laboratory of Dr. Channing Der focused on strategies to disrupt membrane binding of the small GTPase Rheb, in an effort to block aberrant Rheb/mTOR signaling in cancer.
Dr. Hanker pursued postdoctoral training in the laboratory of Dr. Carlos Arteaga at Vanderbilt University Medical Center. During this time, she was awarded a postdoctoral fellowship from the Department of Defense Breast Cancer Research Program and a career development award (K12 award) from the National Cancer Institute. Her postdoctoral studies used laboratory models and human breast cancer xenografts to study mechanisms of resistance to HER2-targeted therapy in HER2-positive breast cancer. More recently, Dr. Hanker identified the HER2 T798I gatekeeper mutation as a mechanism of resistance to HER2-targeted therapy in HER2-mutant breast cancer. Her current work is focused on therapeutic targeting of breast cancer-associated alterations, and delineating mechanisms of resistance to breast cancer targeted therapies, including HER2 inhibitors, antiestrogens, PI3K/AKT inhibitors, and CDK4/6 inhibitors.
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