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lineage plasticity and resistance to AR-targeted therapies through EZH2-dependent epigenetic
reprogramming and upregulation of the “stemness” transcriptional factor SOX2 [23-26] . Similarly, combined
RB1/TP53 loss in patient-derived organoids has been shown to synergistically alter chromatin accessibility,
promoting expression of stemness transcriptional programs while downregulating prostatic
adenocarcinoma and epithelial differentiation programs . Although the exact sequence of events leading to
[27]
the emergence of t-SCNC has not been established, these findings suggest that early genomic events such as
RB1 loss and inactivating TP53 mutations may induce lineage plasticity, with additional genetic and
epigenetic factors leading to subsequent neuroendocrine differentiation and increased cellular
proliferation .
[28]

In addition to the increased frequency of RB1 loss and TP53 mutations that characterize t-SCNC compared
with mCRPC-adenocarcinoma, t-SCNC is also associated with a paucity of genomic alterations involving
the canonical AR signaling pathway, such as amplifications or activating point mutations of the AR gene
locus [3,14,29] . Whole-genome sequencing similarly shows a relative decrease in the incidence of AR enhancer
amplifications among t-SCNC patients compared to those with mCRPC-adenocarcinoma . Interestingly,
[14]
although the overall incidence of mutations involving the AR-coregulator Forkhead box A1 (FOXA1) is
similar across t-SCNC and mCRPC-adenocarcinoma, FOXA1 R219 mutations are significantly enriched in
t-SCNC and have been associated with upregulation of epithelial-mesenchymal-transition (EMT)
program . Key genomic features of t-SCNC are summarized in Table 1, and the role of FOXA1 in lineage
[30]
plasticity is discussed in greater length below.

TRANSCRIPTIONAL PROFILE OF T-SCNC
Despite its genomic overlap with mCRPC-adenocarcinoma, t-SCNC is associated with a distinct
transcriptional profile characterized by the upregulation of stem cell-associated and neuronal
programs [3,11,31,32] . Consistent with the increased incidence of RB1 loss at the genomic level, transcriptional
targets of the E2F transcription factor 1 (E2F1) - negatively regulated by the retinoblastoma protein - are
among the topmost preferentially expressed genes in t-SCNC . On the other hand, genes related to the
[11]
NOTCH signaling pathway, androgen response, and AR activity are frequently downregulated in t-SCNC
relative to mCRPC-adenocarcinoma [3,11,14] . Distinct from de novo SCNC, and somewhat surprisingly,
persistent nuclear AR expression can still be observed in a subset of t-SCNC tumors despite the
downregulation of canonical AR transcriptional programs . This finding highlights the likely role of
[11]
epigenetic modification of AR signaling and the presence of alternative, non-canonical AR transcriptional
programs in t-SCNC.

SRY-related HMG-box gene 2 (SOX2) is a key mediator of RB1 loss/TP53 inactivation-induced lineage
plasticity and has been identified as a master regulator in t-SCNC [9,11,14] SOX2 serves to maintain
pluripotency in human embryonic stem cells and is well known for its ability to reprogram somatic cells
[33]
into induced pluripotent stem cells when combined with OCT4, KLF4 and cMYC . In the normal prostate,
[34]
SOX2 expression is restricted to basal epithelial cells. It is repressed by canonical AR signaling [35-37] and
[38]
conversely upregulated by AR signaling inhibitors . SOX2 upregulation in prostate cancer has been
associated with a poorly-differentiated stem-cell-like phenotype and is necessary for castration-induced
[35]
neuroendocrine differentiation in both PTEN null and RB1/TP3 null models of prostate cancer. In line
[23]
[39]
with its role in normal human development, SOX2 expression in prostate cancer is thought to contribute to
lineage plasticity by promoting the expression of pluripotency genes and repressing master regulators of
adenocarcinoma lineage such as FOXA1 . The exact mechanism through which SOX2 regulates
[40]
transcription has not been elucidated but, interestingly, does not appear to occur through direct DNA
binding. However, SOX2 overexpression induces a dramatic shift in histone H3 methylation status,