The research, led by Zihao Deng, Lifang He, and colleagues under corresponding author Yukun Cui at the Cancer Hospital of Shantou University Medical College, tackles a phenomenon known as lineage plasticity. This is the capacity of cancer cells to shed their original identity and adopt alternative cell states when pressured by therapy, a behavior increasingly recognized as a major driver of treatment resistance in prostate cancer and other tumors. In the androgen receptor-low or androgen receptor-null state, prostate cancer cells build extensive epigenetic barriers: their chromatin, the packaged form of DNA inside the nucleus, becomes inaccessible, and the three-dimensional architecture of the genome locks into a repressive topology that keeps the androgen receptor gene and its regulatory elements silenced. How that locking-in happens, and whether it can be reversed, has remained poorly understood.

KIF11, also known as kinesin family member 11, is best known as a mitotic kinesin, a motor protein that drives spindle assembly during cell division and has long been pursued as a chemotherapy target. Existing KIF11 inhibitors tend to work at cytotoxic doses that halt division in any rapidly proliferating cell. The Shantou team took a different angle. Combining public transcriptomic and epigenomic datasets with their own RNA sequencing, ATAC-seq chromatin accessibility profiling, RNA interference, low-dose pharmacological inhibition with the KIF11 inhibitor ispinesib, chromatin immunoprecipitation, chromosome conformation capture, DNA methylation assays, and reporter and therapeutic-response experiments, they asked what happens to prostate cancer cells when KIF11 activity is reduced gently rather than destroyed completely.

The answer surprised them. In androgen receptor-low and androgen receptor-null prostate cancer models, including PC3 and DU145 cells, either RNAi-mediated depletion or low-dose pharmacological inhibition of KIF11 activated androgen receptor-associated transcriptional programs. The cells began, in effect, to remember who they were supposed to be. Chromatin accessibility increased at androgen receptor regulatory regions, and the team measured higher occupancy of FOXA1 and GRHL2, two pioneering transcription factors that act as gatekeepers of the androgen receptor enhancer, at that key regulatory element. At the same time, the co-activator EP300 and the transcription elongation factor SUPT5H showed increased occupancy at androgen receptor regulatory elements, signaling that the locus was not merely open but actively engaged in productive transcription.

The mechanism went deeper than transcription factor recruitment. Using chromosome conformation capture techniques, the researchers showed that KIF11 inhibition reduced DNA methylation at CTCF motifs, the DNA sequences recognized by the CCCTC-binding factor, an architectural protein that anchors loops in the genome. With methylation lifted, CTCF occupancy rose, and the physical communication between enhancers and the androgen receptor promoter strengthened. In other words, KIF11 inhibition did not simply sprinkle activating marks on the genome; it rebuilt the three-dimensional wiring of the androgen receptor locus, constructing enhancer-promoter loops that bring distant regulatory elements into direct contact with the gene they control.

That topological resetting proved remarkably stable. Once the enhancer-promoter architecture was established, it locked in a sustained androgen receptor transcriptional program and created a feed-forward reinforcement circuit in which the reactivated pathway maintained its own expression. Functionally, this drove what the authors describe as a lineage return: androgen-insensitive, androgen receptor-low or null prostate cancer cells transitioned back into an androgen receptor-responsive transcriptional state. The change was not cosmetic. With the androgen receptor machinery restored, the cells regained the very dependency that antiandrogen drugs exploit.

The therapeutic consequences were tested across multiple model systems. In cell-line experiments, patient-derived castration-resistant prostate cancer organoids, and xenograft models in mice, low-dose KIF11 inhibition combined with enzalutamide or apalutamide produced robust growth suppression in tumors that would normally ignore these drugs. Crucially, the KIF11 inhibition used in these experiments was deliberately kept at low, non-cytotoxic doses, avoiding the broad toxicity that would come with hitting every dividing cell. The strategy is therefore conceptually distinct from conventional chemotherapy: rather than killing cancer cells directly, the treatment reprograms their regulatory architecture so that a second, well-tolerated class of drugs can work again.

The findings carry significant implications for how lineage plasticity-driven resistance might be overcome in the clinic. If a subset of patients with androgen receptor-low or null disease could be identified, perhaps through biopsy-based profiling of KIF11 levels, CTCF methylation status, or androgen receptor locus topology, they might become candidates for a re-sensitization strategy in which short-term KIF11 inhibition converts their tumors into androgen receptor-dependent ones before initiating or resuming antiandrogen therapy. The authors note that Y. Cui and Z. Deng have filed a patent application related to the findings, suggesting momentum toward translational development. At the same time, the work remains at the preclinical stage, and questions about dosing windows, patient selection, and safety in humans will need to be addressed in future studies.

Scientifically, the study adds an important dimension to a growing body of work showing that cancer is as much a disease of genome architecture as of genome sequence. The idea that inhibiting a mitotic motor protein could demethylate CTCF sites, reopen chromatin, reorganize enhancer-promoter loops, and ultimately restore a whole lineage identity illustrates how deeply intertwined cell division machinery, epigenetics, and three-dimensional genome organization really are. For patients with castration-resistant prostate cancer whose tumors have gone androgen-receptor silent, the research offers a conceptually elegant possibility: the door that cancer slammed shut can, with the right molecular key, be opened again, and the treatments already on the shelf may once more find their target.

Subject of Research: KIF11 inhibition as a lineage-remodeling strategy to restore androgen receptor signaling and antiandrogen sensitivity in castration-resistant prostate cancer

Article Title: KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping

Article References: Deng, Z., He, L., Li, J., She, S., Luo, X., Lin, J., Qi, Z., Zhuang, Y., Gao, X., Chi, Z., Xu, Z., Ji, Y., Liu, J., Lin, S. L., & Cui, Y. (2026). KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping. Molecular Cancer. https://doi.org/10.1186/s12943-026-02792-6

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02792-6

Keywords: KIF11, castration-resistant prostate cancer, androgen receptor, lineage plasticity, enhancer-promoter looping, CTCF, epigenetics, enzalutamide, apalutamide, FOXA1, patient-derived organoids, drug resistance

Metastatic prostate cancer (mPC) is often characterized by various genomic alterations in DNA damage repair (DDR) pathways, which play a critical role in the cancer’s progression and response to treatment. Current data suggest that approximately 20% to 25% of patients with advanced prostate cancer exhibit mutations in homologous recombination repair (HRR) genes. As precision medicine becomes increasingly standard in cancer care, identifying the unique molecular signatures within each tumor is paramount to optimizing therapeutic strategies.

The integration of NGS into clinical practice has paved the way for a more personalized approach to cancer treatment, exemplified by the identification of homologous recombination repair deficiencies. Such deficiencies are associated with responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors, marking a pivotal advancement in targeted therapy for prostate cancer patients. Joaquin Mateo, a prominent figure in this study and a medical oncologist at Vall d’Hebron University Hospital, emphasizes that the intersection of precision medicine and prostate cancer treatment manifests in the ability to tailor therapies to specific genetic markers.

However, the widespread adoption of NGS has not been without challenges. As Joaquin Mateo elaborates, issues such as limited tissue availability for sequencing and the extensive resources required for comprehensive genomic profiling impede the broader implementation of these advanced techniques. The quest for complementary methods that enhance the accessibility and practicality of precision medicine in everyday clinical settings remains an active area of research.

In this context, RAD51 emerges as a promising functional biomarker. Produced in-house by the innovative team at VHIO, the RAD51 assay leverages the detection of RAD51 protein to assess HRR status effectively. The mechanistic basis for this approach lies in RAD51’s crucial role within the homologous recombination pathway, a fundamental cellular process responsible for repairing DNA double-strand breaks. By evaluating RAD51 levels in patient samples, clinicians can gain vital insights into a tumor’s HRR capacity, potentially allowing for improved patient stratification and treatment selection.

The current study presents a comprehensive analysis involving 219 biopsies collected from 187 patients diagnosed with advanced prostate cancer. By employing a dual assessment strategy that includes both NGS and the RAD51 test, the research team provides a nuanced understanding of Genomic alterations associated with metastatic disease. Among the frequently altered genes identified were well-known players such as TP53, PTEN, AR, MYC, BRCA1, BRCA2, and ATM, indicating a complex genetic landscape that complicates treatment decisions for oncologists.

The findings of RAD51 immunofluorescence revealed a noteworthy 21% of evaluable samples exhibited a RAD51-low score, signifying HRR deficiency. Strikingly, this low RAD51 expression was correlated with a prominent sensitivity for identifying tumors harboring BRCA1/2 alterations. In clinical terms, patients classified as RAD51-low demonstrated a marked improvement in progression-free survival when treated with PARP inhibitors or platinum-based chemotherapy. This discovery underscores the potential utility of deploying the RAD51 biomarker in routine clinical assessments.

As discussed by Violeta Serra, the Head of VHIO’s Experimental Therapeutics Group and co-corresponding author of the study, the implications of such findings herald a new era of precision medicine in prostate oncology. The utilization of RAD51 testing not only stands to enhance patient outcomes but also offers a viable alternative in scenarios where NGS testing may not be feasible due to tissue constraints.

The financial underpinnings of this groundbreaking research have been supported by an Impact Award from the U.S. Department of Defense, awarded to Joaquin Mateo, alongside crucial funding from AstraZeneca. Additionally, the collaborative efforts of numerous organizations, including the CRIS Cancer Foundation, the Spanish Association against Cancer (AECC), and the European Union through the ERA PerMed initiative, underscore the collective commitment to advancing prostate cancer research.

In summary, the integration of RAD51 protein testing as a complementary strategy in conjunction with NGS presents a compelling advancement in the personalized management of metastatic prostate cancer. This dual approach not only enhances our understanding of the tumor’s molecular landscape but also facilitates more precise patient stratification. As the study emphasizes, the continual identification of innovative biomarkers will be essential in driving the future of oncology and improving patient outcomes across diverse cancer types.

As research in this field progresses, the potential for combining different modalities of testing and treatment will undoubtedly yield deeper insights into the molecular mechanisms underpinning prostate cancer and beyond, ultimately revolutionizing care for patients worldwide.

Subject of Research: RAD51 testing in metastatic prostate cancer
Article Title: Homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional immunofluorescence
News Publication Date: 5-Feb-2025
Web References: Available in the original article.
References: Available in the original article.
Image Credits: Vall d’Hebron Institute of Oncology (VHIO).
Keywords: Prostate cancer, RAD51, precision medicine, biomarkers, DNA damage repair, homologous recombination, PARP inhibitors.