SOX2 — the “plasticity switch” in prostate cancer: how one factor helps tumors change their appearance and elude therapy

A large review of the role of SOX family transcription factors in prostate cancer with a special focus on SOX2 was published in the journal Genes & Diseases. The authors collect and systematize evidence that SOX2 is not just a marker of the stem-like state of cells, but an active driver of growth, invasion, metastasis and drug resistance associated with a higher degree of malignancy and an unfavorable prognosis. Particular attention is paid to linear plasticity: under the pressure of hormonal therapy, the tumor can "slide" from adenocarcinoma to the neuroendocrine phenotype (NEPC) - this is where SOX2 often finds itself in the center of events.

Background of the study

Prostate cancer remains one of the leading causes of cancer mortality in men, and the main clinical problem of late stages is drug resistance after suppression of the androgen signal (ADT/ARTT) and transition to a castration-resistant form. More and more data indicate that tumor "survival" is ensured not only by new mutations, but also by linear plasticity: cells change their identity from the luminal adenocarcinoma phenotype to the androgen-independent neuroendocrine (NEPC), where standard hormonal approaches almost do not work. This transformation is triggered by transcriptional and epigenetic programs under the pressure of therapy.

At the center of these programs are transcription factors of the SOX family, especially SOX2. Normally, it maintains pluripotency and early tissue development, and in a tumor, it is “repurposed” for survival tasks: it enhances proliferation, suppresses apoptosis, promotes invasion and metastasis, increases resistance to treatment, and participates in switching the lineage to the neuroendocrine pathway. At the tissue level, high levels of SOX2 are more common in aggressive variants of prostate cancer and correlate with an unfavorable prognosis.

Mechanistically, SOX2 is integrated into nodes that are often disrupted in patients with “therapy-induced” plasticity: loss of TP53/RB1, decreased AR signaling, PI3K/AKT and MAPK/ERK pathway crossover, as well as epigenetic rewiring and regulation by non-coding RNAs. In such settings, SOX2 facilitates tumor cell escape from AR control and maintains neuroendocrine programs, making the disease refractory to standard hormonal therapy.

Hence the applied question: can SOX2 and related factors be used as biomarkers of plasticity/NEPC risk and as targets for combination therapy (inhibitors of maintenance cascades, epigenetic drugs, oligonucleotide approaches)? The review in Genes & Diseases systematizes the accumulated data on the role of SOX factors in prostate cancer and emphasizes SOX2 as a key “switch” of tumor plasticity - with direct conclusions for patient stratification and design of future clinical trials.

Key Idea: SOX2 as the Architect of Tumor ‘Requalification’

The review highlights that increased SOX2 expression in prostate cancer tissues correlates with an aggressive course and worse outcome, and at the cellular level, the factor:

• enhances proliferation and survival (including through anti-apoptotic programs);
• increases invasion/migration and promotes metastasis;
• forms resistance to therapies (from androgen deprivation to cytotoxics);
• triggers a linear reorganization from castration-resistant prostate cancer (CRPC) to NEPC.
  On the molecular map, this is associated with the cross-pathways of PI3K/AKT, MAPK/ERK, Hedgehog, interaction with embryonic pluripotency factors and regulation by non-coding RNAs.

How exactly does SOX2 pull the strings?

Normally, SOX2 is important for prostate development and maintaining stem status. In a tumor, it reuses the same “tools”:

• Lineage plasticity and EMT. SOX2 is involved in the transition to a neuroendocrine phenotype, maintains an intermediate stem-like state, and facilitates epithelial-mesenchymal transition. A number of studies have described the association of SOX2 with neuronal factors (e.g., ASCL1) during CRPC→NEPC conversion.
• Growth signaling axes. Activation of PI3K/AKT and MAPK/ERK helps cells divide and avoid apoptosis; Hedgehog often enhances the same course of events, with SOX2 possibly acting downstream.
• Regulation by non-coding RNAs. MicroRNAs and long non-coding RNAs fine-tune the levels of SOX2 and its targets; changing this field is a typical tumor technique for rapid adaptation.

What does this mean for the clinic - three practical vectors

1. Biomarker of disease risk and trajectory. Elevated SOX2 is associated with a more aggressive course, and expression maps may suggest where to expect neuroendocrine conversion and drug resistance. 2) Therapeutic target. Several approaches are conceptually available: suppression of SOX2 transcriptional activity, targeting supporting pathways (PI3K/AKT, MAPK/ERK, Hedgehog), and modulation of its regulating non-coding RNAs. 3) Combination regimens. This review highlights the logic of early combination of anti-SOX2 strategies with androgen-targeted therapy in subgroups at high risk of plasticity. This is a subject for phase II/III clinical trials.

Why did the topic come up now?

The “epidemic” of castration-resistant and neuroendocrine prostate cancer continues, where standard hormonal regimens are rapidly losing their effectiveness. Against this backdrop, both academic reviews and press materials emphasize the role of SOX2 as a central “switch” that helps tumors survive therapeutic pressure, change their identity, and continue to grow. To develop targeted interventions, it is important not so much to “switch off” a single protein as to disrupt its network of interactions and sources of plasticity.

What else needs to be tested (research roadmap)

• Prospective validation of SOX2 as a prognostic marker (including NEPC risk) in multicenter cohorts.
• Functional tests of combinations (PI3K/AKT inhibitors, MAPK/ERK inhibitors, BET modulators, oligonucleotides against regulatory RNAs, PROTACs/degraders) in models where plasticity is induced by clinically relevant therapeutic pressure.
• Diagnostic panels: joint assessment of SOX2 with AR signaling, ASCL1, epigenetic and miRNA signatures for patient selection in studies.
  These steps will help transform the conceptual target into a practical tool for stratification and treatment.

Important Disclaimers

This is a review that combines and interprets disparate data (cell models, animal experiments, tissue marker studies, retrospective clinics). The causality and scale of effects in real practice require randomized trials and standardized diagnostics of plasticity. Nevertheless, the consensus of different sources - from PubMed abstracts to independent reviews on SOX2 - converges: it is one of the key regulators of the aggressive course of prostate cancer and a worthy target for targeted oncology.

Original source: Du G., Huang X., Su P., Yang Y., Chen S., Huang T., Zhang N. The role of SOX transcription factors in prostate cancer: Focusing on SOX2. Genes & Diseases (2025) 12(6):101692. DOI: 10.1016/j.gendis.2025.101692.