Molecular switch linked to lineage plasticity, therapy resistance: Newsroom

Molecular switch linked to lineage plasticity, therapy resistance: Newsroom

Molecular switch linked to lineage plasticity, therapy resistance: Newsroom

Researchers at UT Southwestern have identified a new mechanism involved in tumor cells, shown in this 3D illustration, offering insights that could lead to better treatments for prostate cancer, the most common cancer among men. (Photo credit: Getty Images)

DALLAS – June 4, 2024 – Two genes working in tandem play a critical role in shaping the identity and behavior of prostate cancer cells and their response to treatment, UT Southwestern Medical Center researchers report. The findings, published in Cancer Discovery, offer crucial insights into how cancer cells evade the current standard-of-care treatments and provide a potential target for the development of novel prostate cancer therapies.

Ping Mu, Ph.D.

Ping Mu, Ph.D., Assistant Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, is a Deborah and W. A. “Tex” Moncrief, Jr. Scholar in Medical Research.

“Our study reveals a new genetic and molecular process that controls how tumor cells change their type and respond to treatment,” said study leader Ping Mu, Ph.D., Assistant Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “These important discoveries enhance our understanding of what drives drug resistance and introduce a new approach for treating prostate cancer.”

Nearly 1 out of every 8 men will get prostate cancer during their lifetime, making it the most common cancer among men, according to the American Cancer Society.

Prostate cancer’s ability to adapt has proved a formidable challenge, with therapy resistance emerging as a significant obstacle. Advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), is particularly difficult due to its capacity to develop resistance to conventional therapies, such as androgen receptor (AR) inhibitors.

This resistance can arise due to lineage plasticity, where cancer cells undergo “identity switches,” enabling them to evade targeted treatments. Lineage plasticity allows cancer cells to switch from their original luminal lineage, driven by androgen receptor (AR) signaling, to alternative lineages, such as neuroendocrine or stem-like phenotypes, which are resistant to AR-targeted therapies originally designed to target their previous identities.

In this study, researchers identified a deficiency of Zinc Finger Protein 397 (ZNF397) as a critical trigger for this transformation in prostate cancer cells. This deficiency prompts a shift from a reliance on AR signaling for cell growth (the luminal lineage) to increased dependence on activity involving the gene Ten Eleven Translocation 2 (TET2), which encodes an enzyme that regulates DNA methylation, a critical epigenetic mechanism. The transition consequently renders cancer cells more flexible and adaptable, ultimately leaving them resistant to therapies targeting AR signaling.

The research also revealed the pivotal role of TET2 in driving epigenetic rewiring, which contributes to lineage plasticity and therapy resistance in prostate cancer, shedding light on how prostate cancer cells can adapt through epigenetic reprogramming. In addition, the study demonstrates that inhibiting TET2 can reverse resistance to AR-targeted therapies in ZNF397-deficient tumors. By genetically and pharmacologically inactivating TET2, the researchers effectively reversed resistance to AR-targeted therapies in ZNF397-deficient tumors.

The study builds upon previous research from the Mu Lab, furthering the understanding of lineage plasticity and drug resistance mechanisms and paving the way for personalized treatment strategies tailored to combat lineage plasticity-driven therapy resistance in prostate cancer.

“The possibility of reversing this type of resistance by targeting TET2 with drugs offers new paths for developing treatments for patients with advanced prostate cancer,” Dr. Mu said. “These insights could lead to clinical trials testing TET2 inhibitors in treating metastatic castration-resistant prostate cancer patients, potentially improving treatment results and increasing survival rates.”

Other UTSW researchers who contributed to this study include Ganesh V. Raj, M.D., Ph.D., Professor of Urology and Pharmacology; Carlos L. Arteaga, M.D., Professor and Director of the Simmons Cancer Center and Associate Dean of Oncology Programs; Ariella B. Hanker, Ph.D., Assistant Professor in the Simmons Cancer Center and of Internal Medicine; Tao Wang, Ph.D., Associate Professor in the Peter O’Donnell Jr. School of Public Health and the Center for the Genetics of Host Defense; Su Deng, Ph.D., Instructor of Molecular Biology; postdoctoral researchers Yaru Xu, Ph.D., Xiang Li, Ph.D., Xiaoling Li, Ph.D., and Quanhui Xu, Ph.D.; graduate student researchers Yuqiu Yang, M.S., Choushi Wang, B.S., Julisa Gonzalez, B.S., Atreyi Mukherji, B.S., Carla Rodriguez-Tirado, B.S., and Mia Hofstad, B.S.; Yuyin Jiang, B.S., Research Technician; and Lauren A. Metang, M.S., Senior Research Associate.

Dr. Mu is a Deborah and W. A. “Tex” Moncrief, Jr. Scholar in Medical Research at UTSW.

This study was funded by grants from the National Cancer Institute/National Institutes of Health (5R00CA218885 and 1R37CA258730, 1R01CA258584, T32C124334, 1F31CA261019-01A1), the U.S. Department of Defense (W81XWH-18-1-0411 and W81XWH21-1-0520, W81XWH21-1-0418), the Cancer Prevention & Research Institute of Texas (RR170050, RP220473, RP230363), the Prostate Cancer Foundation (17YOUN12 and 21YOUN10), The Welch Foundation (I-2005-20190330), a UT Southwestern Harold C. Simmons Comprehensive Cancer Center Pilot Award, the Simmons Cancer Center Data Science Shared Resource, the Terry Fox New Frontiers Program Project Grant (PPG19-1090), the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543), and the Life Sciences Research Foundation.

Disclosures are listed in the study.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 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 more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

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