TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

Abstract

26In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-27 generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical 28 benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To 29 determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and 30 found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP 31 human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies 32 demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated 33 neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in 34 the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide 35 resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance 36 in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially 37 reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of 38 metastatic CaP were examined, a positive correlation was found between the expression levels of 39 TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide 40 resistance via NED in CaP. 42 Prostate cancer (CaP) is the most common non-cutaneous cancer diagnosed among men and the 43 second leading cause of male cancer deaths in the United States (1). In 2017, it is estimated that 44 26,730 men died from CaP. Although radiation and surgery are quite effective for localized disease, 45 approximately 30% eventually recur following a definitive therapy. More importantly, there is no 46 effective cure for men who present with metastatic CaP as the 5-year relative survival rate is only 47 29% (1). In patients with a metastatic disease, medical or surgical castration is generally the 48 accepted first-line therapy. Yet, castration-resistant prostate cancer (CRPC) eventually emerges 49 with a median time of 18-24 months (2, 3). Once CRPC develops, secondary hormonal 50 manipulation, immunotherapy, and chemotherapy are marginally effective and the average life 51 expectancy is ~5 years (4, 5). 52Enzalutamide is a FDA-approved second-generation androgen receptor (AR) antagonist 53 that blocks ligand binding, nuclear translocation, DNA binding, and coactivator recruitment of 54 ARs (6). In multiple clinical trials, enzalutamide has been shown to prolong overall and 55 progression-free survival, improve patient-reported quality of life, and delay the development of 56 skeletal-related complications in men with metastatic CRPC who are chemotherapy naïve or have 57 previously received docetaxel (7-9). However, despite the significant initial therapeutic benefits 58 of enzalutamide, resistance inevitably occurs with a median time of 4.8 months. Although the 59 precise mechanistic details underlying the emergence of enzalutamide resistance is largely 60 ...

Single-cell RNA sequencing reveals spatiotemporal heterogeneity and malignant progression in pancreatic neuroendocrine tumor

“…In terms of transcriptional regulation, the SCENIC analysis on all malignant subtypes showed specific enhanced activity of TCF4 (transcription factor 4) in the subtype 3 (Supplementary Figure S1D). It is well known that TCF4 is a gene which was found to be abundantly expressed during neural development, 24 and TCF4 was also involved in neuroendocrine differentiation of tumor cells, 25 which was consistent with the above findings about the prominent feature of neuroendocrine in subtype 3. Additionally, TCF4 has been found to be associated with tumorigenesis in a variety of tumors and was a potential molecular target against kinds of cancer, [26][27][28][29] suggesting that TCF4 may be an intervention target for the subgroup 3.…”

WLS-Wnt signaling promotes neuroendocrine prostate cancer

“…We investigated the effects of WLS KD on the proliferation of three NE or NE-like PC cell lines, C4-2B ENZR , 22Rv1 and PC-3. The 22Rv1 cell line was derived from a human prostate adenocarcinoma xenograft displaying an NE phenotype (Huss et al, 2004;Sramkoski et al, 1999), and showed upregulation of NE markers such as NSE under hypoxia or combined androgen deprivation and ENZ treatment (Lee et al, 2019;Qi et al, 2010). The 22Rv1 cell line also expresses AR and AR splice variants rendering cells resistant to ENZ .…”

Transcription factor 4 expression in circulating tumor cells from castration‐resistant prostate cancer

“…Studies have reported associations of ENZ therapy with the transcriptional dysregulation and genetic abnormalities causing NED 9–11 . We also previously revealed that TCF4 induces NED during resistance acquisition to ENZ therapy 6 . Therefore, the expression of TCF4 in PC cells could monitor antiandrogen‐mediated neuroendocrine modulation, contributing to treatment resistance.…”