Researchers report that treatment resistance in advanced prostate cancer is driven by epigenetic lineage plasticity rather than genetic mutations, raising new possibilities for combination therapies and biomarker development in clinical laboratories.
Scientists at the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University have identified a molecular mechanism that helps explain why advanced prostate cancers often become resistant to modern hormone-based therapies—and, importantly, how that resistance may be reversed. The findings, published in Nature, describe how prostate tumor cells evade treatment through epigenetic reprogramming rather than genetic mutation, and present preclinical evidence for a drug strategy that could restore treatment sensitivity.
For clinical laboratory professionals, the study highlights the growing relevance of epigenetic regulation, lineage plasticity, and biomarker-driven therapeutic strategies in oncology.
From Hormone Therapy to Lineage Switching
Over the past decade, androgen receptor (AR) inhibitors have become the standard of care for advanced prostate cancer. While initially effective, these therapies frequently drive tumors to adopt a neuroendocrine-like state, a highly aggressive phenotype that no longer depends on androgen signaling and is largely resistant to existing drugs. This transition has posed a longstanding puzzle for cancer biologists and clinicians alike, as it occurs without obvious DNA mutations.
The research builds on decades of work by Michael Shen, PhD, co-leader of the tumor biology and microenvironment program at HICCC, who studies “lineage plasticity”—the ability of cancer cells to change identity under therapeutic pressure. Prior work from Shen’s lab showed that this lineage shift is driven by epigenetic changes rather than permanent genetic alterations, pointing to reversible factors.
To identify the epigenetic drivers, Shen partnered with other Columbia researchers. The team homed in on NSD2, a gene that regulates cellular processes but can also cause cancers during abnormal activity. (Photo credit: Columbia University)
Targeting an “Undruggable” Enzyme to Restore Drug Sensitivity
NSD2 had long been considered “undruggable,” complicating efforts to translate the discovery into a therapeutic strategy. However, recent advances in small-molecule inhibitor development changed that outlook. Using a newly developed NSD2 inhibitor, the researchers demonstrated in prostate cancer models that blocking NSD2 caused neuroendocrine tumors to lose their resistance to therapies.
While NSD2 inhibition alone did not kill tumor cells, its impact was dramatic when combined with other inhibitors. The combination therapy restored sensitivity to standard hormone treatments, effectively resensitizing previously resistant cancers.
For the clinical laboratory community, these findings underscore the importance of epigenetic markers in cancer diagnostics. The ability to distinguish lineage states—and potentially monitor transitions between them—could influence future testing strategies, companion diagnostics, and treatment selection.
More broadly, the study provides one of the clearest demonstrations to date that epigenetically driven treatment resistance can be reversed. Because lineage plasticity is common across multiple tumor types, including small cell lung cancer, the NSD2 pathway may represent a broader therapeutic and diagnostic target.
As these findings move toward clinical testing, laboratories may play a central role in translating epigenetic insights into actionable oncology care.
The CAP- and CLIA-validated microRNA-371a-3P assay promises earlier detection, fewer CT scans, and more precise treatment decisions for a high-risk patient population.
According to a press release, UC San Diego Health has become the first health system in the United States to offer a clinically validated blood test for testicular cancer. This advance could potentially redefine diagnostic workflows, reduce reliance on imaging, and sharpen treatment decisions for a patient population that often faces both overtreatment and missed recurrences.
The assay, more than a decade in development, measures microRNA-371a-3P, a biomarker shown to detect the presence of testicular cancer cells with about 90% accuracy. Until now, clinicians and clinical laboratories have had limited tools to determine which patients require surgery, chemotherapy, or simply surveillance, especially when imaging is inconclusive.
Testicular cancer strikes roughly 10,000 people annually, primarily men between 18 and 45, yet existing serum markers fail to capture the majority of cases. As a result, laboratories and oncologists have historically struggled with staging uncertainty, unnecessary chemotherapy, and delayed recognition of recurrence. About one-third of patients experience relapses after orchiectomy despite normal CT imaging.
The press release explained that the biomarker’s sensitivity and specificity offer a clearer, earlier signal of active cancer biology—information that can materially change treatment plans.
Further, the test can be used across the care continuum. Before surgery, it can help confirm whether an abnormal testis is malignant and guide surgical decision-making. Post-operatively, it can help determine which patients truly need systemic therapy or further intervention. During surveillance, it may detect recurrence earlier than imaging, allowing less intensive and more precisely timed treatment.
For laboratories, one of the most consequential implications is the potential to reduce the reliance on repeated CT scans, as they carry radiation exposure, cost burdens, and logistical challenges. A validated blood-based alternative, if adopted more widely, could shift surveillance algorithms across health systems.
A Model for Translational Collaboration
The test is currently available for patients at UC San Diego Health and will open to external referrals later this year, allowing outside clinicians and pathology departments to submit samples. It is fully CAP-accredited and CLIA-certified, positioning it for broader adoption by cancer centers seeking higher-resolution molecular insight without expanding imaging capacity.
“This breakthrough represents the kind of investment in innovation that can save lives while improving quality of life for cancer survivors,” said Diane Simeone, MD, director of the Moores Cancer Center at UC San Diego Health. (Photo credit: UC San Diego Health)
For the urology and oncology teams, the test represents years of translational research. For laboratories, it represents a milestone in bringing microRNA-based diagnostics into routine clinical use.
Integrating Results into Multidisciplinary Care
Each test result will feed into UC San Diego Health’s molecular tumor board, a multidisciplinary group that meets every two weeks to review every patient case and interpret biomarker findings in the context of clinical, imaging, and pathological data. For laboratory professionals, this embedded oversight ensures that results are used appropriately and helps refine test performance insights over time.
For labs nationwide, the launch signals a turning point: a real-world, regulated microRNA test with immediate clinical impact—and a template for how laboratory medicine can lead in closing long-standing diagnostic gaps.
This article was created with the assistance of Generative AI and has undergone editorial review before publishing.
