Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.

[1]  A. Chinnaiyan,et al.  LSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function , 2023, JCI insight.

[2]  Hisashi Tanaka,et al.  Autonomous action and cooperativity between the ONECUT2 transcription factor and its 3′ untranslated region , 2023, Frontiers in Cell and Developmental Biology.

[3]  Lin Li,et al.  Neurokinin-1 receptor drives PKCɑ-AURKA/N-Myc signaling to facilitate the neuroendocrine progression of prostate cancer , 2023, Cell death & disease.

[4]  Jiaoti Huang,et al.  CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer , 2023, Cell death & disease.

[5]  R. Ummanni,et al.  MicroRNA‐147b induces neuroendocrine differentiation of prostate cancer cells by targeting ribosomal protein RPS15A , 2023, The Prostate.

[6]  Jiaoti Huang,et al.  Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer. , 2023, Redox biology.

[7]  Lei Ding,et al.  Trigred motif 36 regulates neuroendocrine differentiation of prostate cancer via HK2 ubiquitination and GPx4 deficiency , 2023, Cancer science.

[8]  J. Hsieh,et al.  A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer , 2023, Pharmaceutics.

[9]  S. Obika,et al.  An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells , 2023, Cancer Cell International.

[10]  A. Jemal,et al.  Cancer statistics, 2023 , 2023, CA: a cancer journal for clinicians.

[11]  S. Terry,et al.  The Neuropilin-1/PKC axis promotes neuroendocrine differentiation and drug resistance of prostate cancer , 2022, British Journal of Cancer.

[12]  A. Cherkasov,et al.  Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness , 2022, Cancers.

[13]  Junke Zheng,et al.  FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer. , 2022, Cancer cell.

[14]  H. Beltran,et al.  DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms , 2022, The oncologist.

[15]  C. Li,et al.  Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer , 2022, Frontiers in Cell and Developmental Biology.

[16]  R. Plummer,et al.  Clinical activity of CC‐90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies , 2022, Cancer.

[17]  F. Ban,et al.  Development of VPC-70619, a Small-Molecule N-Myc Inhibitor as a Potential Therapy for Neuroendocrine Prostate Cancer , 2022, International journal of molecular sciences.

[18]  G. Raj,et al.  The central role of Sphingosine kinase 1 in the development of neuroendocrine prostate cancer (NEPC): A new targeted therapy of NEPC , 2022, Clinical and translational medicine.

[19]  R. Ummanni,et al.  Activation of TGF-β - SMAD2 signaling by IL-6 drives neuroendocrine differentiation of prostate cancer through p38MAPK. , 2022, Cellular signalling.

[20]  Yuzhuo Wang,et al.  Molecular events in neuroendocrine prostate cancer development , 2021, Nature Reviews Urology.

[21]  J. Bono,et al.  Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial , 2021, The Lancet.

[22]  B. Broom,et al.  PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer , 2021, Molecular Cancer Therapeutics.

[23]  P. Nelson,et al.  BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program , 2021, Clinical Cancer Research.

[24]  H. Beltran,et al.  The treatment landscape of metastatic prostate cancer. , 2021, Cancer letters.

[25]  H. Beltran,et al.  Therapy considerations in neuroendocrine prostate cancer: what next? , 2021, Endocrine-related cancer.

[26]  Alisha Dhiman,et al.  A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation , 2021, Chembiochem : a European journal of chemical biology.

[27]  Zhou Wang,et al.  Targeting ADT-Induced Activation of the E3 Ubiquitin Ligase Siah2 to Delay the Occurrence of Castration-Resistant Prostate Cancer , 2021, Frontiers in Oncology.

[28]  Yuzhuo Wang,et al.  The evolutionarily conserved long non‐coding RNA LINC00261 drives neuroendocrine prostate cancer proliferation and metastasis via distinct nuclear and cytoplasmic mechanisms , 2021, Molecular oncology.

[29]  G. Spoettl,et al.  Antitumoral Activity of the MEK Inhibitor Trametinib (TMT212) Alone and in Combination with the CDK4/6 Inhibitor Ribociclib (LEE011) in Neuroendocrine Tumor Cells In Vitro , 2021, Cancers.

[30]  K. Souček,et al.  Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade , 2021, International journal of molecular sciences.

[31]  H. Beltran,et al.  Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer , 2021, Cancer Research.

[32]  Wen-Chih Cheng,et al.  Current advances of targeting epigenetic modifications in neuroendocrine prostate cancer , 2021, Tzu chi medical journal.

[33]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[34]  H. Beltran,et al.  Clinical Considerations for the Management of Androgen Indifferent Prostate Cancer , 2021, Prostate Cancer and Prostatic Diseases.

[35]  P. Nelson,et al.  Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature , 2021, PloS one.

[36]  Z. Dong,et al.  Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy , 2021, Molecular cancer.

[37]  H. Beltran,et al.  Clinical and Biological Features of Neuroendocrine Prostate Cancer , 2021, Current Oncology Reports.

[38]  Jiaoti Huang,et al.  Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance , 2021, Communications biology.

[39]  A. Zoubeidi,et al.  Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer. , 2021, Cell reports.

[40]  A. Gao,et al.  WLS-Wnt signaling promotes neuroendocrine prostate cancer , 2021, iScience.

[41]  F. Ban,et al.  Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer , 2020, International journal of molecular sciences.

[42]  J. Qin,et al.  Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2 , 2020, The Journal of pathology.

[43]  R. Dahiya,et al.  MicroRNA determinants of neuroendocrine differentiation in metastatic castration-resistant prostate cancer , 2020, Oncogene.

[44]  G. Pond,et al.  Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials. , 2020, European urology oncology.

[45]  Weijian Guo,et al.  EZH2: a novel target for cancer treatment , 2020, Journal of Hematology & Oncology.

[46]  A. Pantuck,et al.  A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer , 2020, Clinical Cancer Research.

[47]  M. Gleave,et al.  LIN28B promotes the development of neuroendocrine prostate cancer. , 2020, The Journal of clinical investigation.

[48]  B. Győrffy,et al.  BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer , 2020, Prostate Cancer and Prostatic Diseases.

[49]  P. Nelson,et al.  Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4 , 2020, Neoplasia.

[50]  A. Rizzino,et al.  Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide , 2020, Journal of cellular physiology.

[51]  M. Rubin,et al.  Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity , 2020, Nature Communications.

[52]  F. Feng,et al.  Neddylation inactivation represses androgen receptor transcription and inhibits growth, survival and invasion of prostate cancer cells , 2020, Neoplasia.

[53]  O. Elemento,et al.  Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. , 2020, The Journal of clinical investigation.

[54]  Q. Hu,et al.  MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer , 2020, Nature Communications.

[55]  K. Rajapakshe,et al.  A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer , 2020, Clinical Cancer Research.

[56]  J. Brooks,et al.  Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1 , 2020, Proceedings of the National Academy of Sciences.

[57]  A. Zoubeidi,et al.  The epigenetic and transcriptional landscape of neuroendocrine prostate cancer. , 2019, Endocrine-related cancer.

[58]  Chunxiao Wu,et al.  SOX2 has dual functions as a regulator in the progression of neuroendocrine prostate cancer , 2019, Laboratory Investigation.

[59]  O. Elemento,et al.  Clinical features of neuroendocrine prostate cancer. , 2019, European journal of cancer.

[60]  U. Lo,et al.  The paracrine induction of prostate cancer progression by caveolin-1 , 2019, Cell Death & Disease.

[61]  Lavanya Moparthi,et al.  Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer , 2019, Proceedings of the National Academy of Sciences.

[62]  L. Chouchane,et al.  Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer , 2019, Cell Death Discovery.

[63]  R. Schiff,et al.  The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells , 2019, Proceedings of the National Academy of Sciences.

[64]  A. Sboner,et al.  PARP Inhibition Suppresses GR–MYCN–CDK5–RB1–E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer , 2019, Clinical Cancer Research.

[65]  M. Loda,et al.  The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance , 2019, Clinical Cancer Research.

[66]  A. Zoubeidi,et al.  PEG10 is associated with treatment-induced neuroendocrine prostate cancer. , 2019, Journal of molecular endocrinology.

[67]  A. Tinker,et al.  A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205. , 2019, Clinical genitourinary cancer.

[68]  R. Liddington,et al.  Identification and characterization of small molecule inhibitors of the ubiquitin ligases Siah1/2 in melanoma and prostate cancer cells. , 2019, Cancer letters.

[69]  P. Nelson,et al.  Targeting RET Kinase in Neuroendocrine Prostate Cancer , 2019, Molecular Cancer Research.

[70]  Xu Zhang,et al.  Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46 , 2019, Clinical Cancer Research.

[71]  O. Elemento,et al.  Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer , 2019, Science Translational Medicine.

[72]  Christian M. Metallo,et al.  Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. , 2019, Cancer cell.

[73]  Chawnshang Chang,et al.  Neurotensin and its receptors mediate neuroendocrine transdifferentiation in prostate cancer , 2019, Oncogene.

[74]  C. Liang,et al.  N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway , 2019, Molecular Cancer.

[75]  T. H. van der Kwast,et al.  ONECUT2 is a driver of neuroendocrine prostate cancer , 2019, Nature Communications.

[76]  M. Rubin,et al.  NSD2 is a conserved driver of metastatic prostate cancer progression , 2018, Nature Communications.

[77]  Simon G. Coetzee,et al.  ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis , 2018, Nature Medicine.

[78]  Zheng Wang,et al.  Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers , 2018, Nature Communications.

[79]  M. Rubin,et al.  A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers , 2018, Clinical Cancer Research.

[80]  C. Rudin,et al.  Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition , 2019, Science Signaling.

[81]  R. Hohl,et al.  Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models , 2018, The Prostate.

[82]  Yuxin Tang,et al.  A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network , 2018, EBioMedicine.

[83]  C. Tepper,et al.  KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC , 2018, Oncogene.

[84]  A. Font,et al.  Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss , 2018, Clinical Cancer Research.

[85]  Joshua M. Stuart,et al.  Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer , 2018, Cell.

[86]  Kwok-Kin Wong,et al.  Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate. , 2018, JCI insight.

[87]  C. Collins,et al.  Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer , 2018, Cancer medicine.

[88]  C. Collins,et al.  Heterochromatin Protein 1α Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer. , 2018, Cancer research.

[89]  William H. Bisson,et al.  LSD1 activates a lethal prostate cancer gene network independently of its demethylase function , 2018, Proceedings of the National Academy of Sciences.

[90]  F. Zheng,et al.  HOTAIR-mediated reciprocal regulation of EZH2 and DNMT1 contribute to polyphyllin I-inhibited growth of castration-resistant prostate cancer cells in vitro and in vivo. , 2018, Biochimica et biophysica acta. General subjects.

[91]  A. Zoubeidi,et al.  Cellular plasticity and the neuroendocrine phenotype in prostate cancer , 2018, Nature Reviews Urology.

[92]  Ming He,et al.  SIRT1 contributes to neuroendocrine differentiation of prostate cancer , 2017, Oncotarget.

[93]  M. Rubin,et al.  Differential impact of RB status on E2F1 reprogramming in human cancer , 2017, The Journal of clinical investigation.

[94]  G. Peng,et al.  Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer , 2017, Clinical Cancer Research.

[95]  A. Chinnaiyan,et al.  Targeting the MYCN–PARP–DNA Damage Response Pathway in Neuroendocrine Prostate Cancer , 2017, Clinical Cancer Research.

[96]  F. Montorsi,et al.  Contemporary Incidence and Cancer Control Outcomes of Primary Neuroendocrine Prostate Cancer: A SEER Database Analysis , 2017, Clinical genitourinary cancer.

[97]  A. Armstrong,et al.  Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. , 2017, European journal of cancer.

[98]  R. Buttyan,et al.  Implications of PI3K/AKT inhibition on REST protein stability and neuroendocrine phenotype acquisition in prostate cancer cells , 2017, Oncotarget.

[99]  Wei Yu Chen,et al.  Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis , 2017, Oncogene.

[100]  A. Tewari,et al.  Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications , 2017, Translational oncology.

[101]  A. Hsieh,et al.  A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer , 2017, The oncologist.

[102]  C. Pan,et al.  REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer , 2017, Scientific Reports.

[103]  D. Markovitz,et al.  DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis , 2017, Nature Communications.

[104]  Ximing J. Yang,et al.  FOXA1 inhibits prostate cancer neuroendocrine differentiation , 2017, Oncogene.

[105]  Henry W. Long,et al.  Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance , 2017, Science.

[106]  M. Eilers,et al.  Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors , 2016, Proceedings of the National Academy of Sciences.

[107]  Kaitlyn M. Gayvert,et al.  N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. , 2016, Cancer cell.

[108]  L. Fazli,et al.  c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer , 2016, Oncotarget.

[109]  S. Tomlins,et al.  The Role of Next-Generation Sequencing in Castration-Resistant Prostate Cancer Treatment , 2016, Cancer journal.

[110]  Joshua M. Stuart,et al.  N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. , 2016, Cancer cell.

[111]  Matteo Benelli,et al.  Divergent clonal evolution of castration resistant neuroendocrine prostate cancer , 2016, Nature Medicine.

[112]  T. Graeber,et al.  The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma , 2016, Molecular Cancer Research.

[113]  C. Logothetis,et al.  Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties , 2016, Oncogene.

[114]  H. Beltran,et al.  The Initial Detection and Partial Characterization of Circulating Tumor Cells in Neuroendocrine Prostate Cancer , 2015, Clinical Cancer Research.

[115]  Jayoung Kim,et al.  SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer , 2015, Oncotarget.

[116]  V. Arora,et al.  Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer , 2015, Nature Reviews Cancer.

[117]  L. Manzoli,et al.  SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis , 2015, Oncotarget.

[118]  Robert H. Bell,et al.  The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer. , 2015, Cell reports.

[119]  Hong-Chiang Chang,et al.  Anti‐androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals , 2015, Molecular oncology.

[120]  P. Nelson,et al.  SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer , 2015, Clinical Cancer Research.

[121]  W. Lam,et al.  Polycomb-mediated silencing in neuroendocrine prostate cancer , 2015, Clinical Epigenetics.

[122]  Runsheng Li,et al.  A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells , 2015, Oncotarget.

[123]  M. Kumar,et al.  Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation , 2015, Clinical Cancer Research.

[124]  M. Tupone,et al.  SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression , 2015, Oncotarget.

[125]  Robert H. Bell,et al.  Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer , 2014, Oncotarget.

[126]  David C. Smith,et al.  Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[127]  Yezi Zhu,et al.  Interleukin‐6 induces neuroendocrine differentiation (NED) through suppression of RE‐1 silencing transcription factor (REST) , 2014, The Prostate.

[128]  N. Houédé,et al.  Characterization of prostate neuroendocrine cancers and therapeutic management: a literature review , 2014, Prostate Cancer and Prostatic Disease.

[129]  Zhaohui S. Qin,et al.  Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer , 2014, Nature.

[130]  M. Rubin,et al.  Aggressive Variants of Castration-Resistant Prostate Cancer , 2014, Clinical Cancer Research.

[131]  Jun Xie,et al.  Down-regulation of RE-1 silencing transcription factor (REST) in advanced prostate cancer by hypoxia-induced miR-106b~25. , 2014, Experimental cell research.

[132]  A. Tolcher,et al.  Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors , 2014, Journal of Hematology & Oncology.

[133]  D. Zheng,et al.  Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade , 2013, Cell.

[134]  Joaquim Bellmunt,et al.  Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. , 2013, The Lancet. Oncology.

[135]  C. Collins,et al.  REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer , 2013, Nucleic acids research.

[136]  N. Maitland,et al.  JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. , 2013, Cancer research.

[137]  W. Ye,et al.  A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy , 2013, Anti-cancer drugs.

[138]  J. Haefliger,et al.  Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells. , 2013, Endocrine-related cancer.

[139]  F. Cappuzzo,et al.  Randomized phase II study of danusertib in patients with metastatic castration‐resistant prostate cancer after docetaxel failure , 2013, BJU international.

[140]  Zhaohui S. Qin,et al.  Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. , 2013, Molecular cell.

[141]  J. Angulo,et al.  EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway. , 2012, Carcinogenesis.

[142]  P. Humphrey.  Histological variants of prostatic carcinoma and their significance , 2012, Histopathology.

[143]  M. Gerstein,et al.  Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. , 2011, Cancer discovery.

[144]  G. Sonpavde,et al.  Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer. , 2011, Urologic oncology.

[145]  P. Nelson,et al.  Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. , 2011, Cancer cell.

[146]  Wun-Jae Kim,et al.  Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6‐IL6 Loop , 2011, The Prostate.

[147]  D. Tindall,et al.  Alternatively spliced androgen receptor variants. , 2011, Endocrine-related cancer.

[148]  H. Bonkhoff.  Factors Implicated in Radiation Therapy Failure and Radiosensitization of Prostate Cancer , 2011, Prostate cancer.

[149]  Elizabeth D. Wederell,et al.  Retinoblastoma-binding proteins 4 and 9 are important for human pluripotent stem cell maintenance. , 2011, Experimental hematology.

[150]  Arturo Molina,et al.  Abiraterone and increased survival in metastatic prostate cancer. , 2011, The New England journal of medicine.

[151]  R. Cardiff,et al.  Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. , 2010, Cancer cell.

[152]  L. Chung,et al.  Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells , 2010, The Prostate.

[153]  J. Pinski,et al.  Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer , 2010, Clinical Cancer Research.

[154]  Christophe Massard,et al.  Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer , 2009, Clinical Cancer Research.

[155]  K. Yeung,et al.  Pivotal roles of snail inhibition and RKIP induction by the proteasome inhibitor NPI-0052 in tumor cell chemoimmunosensitization. , 2009, Cancer research.

[156]  D. Spandidos,et al.  Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction , 2009, Oncogene.

[157]  R. M. Henke,et al.  Ascl1 and Neurog2 form novel complexes and regulate Delta-like3 (Dll3) expression in the neural tube. , 2009, Developmental biology.

[158]  Bruce Montgomery,et al.  Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion , 2009, Nature Clinical Practice Urology.

[159]  Vincenza Dolo,et al.  Chronic azacitidine treatment results in differentiating effects, sensitizes against bicalutamide in androgen‐independent prostate cancer cells , 2008, The Prostate.

[160]  Zhengxin Wang,et al.  Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. , 2008, Cancer research.

[161]  Olov Sterner,et al.  Galiellalactone is a novel therapeutic candidate against hormone‐refractory prostate cancer expressing activated Stat3 , 2008, The Prostate.

[162]  K. Iczkowski,et al.  Inhibition of Macrophage Migration Inhibitory Factor or Its Receptor (CD74) Attenuates Growth and Invasion of DU-145 Prostate Cancer Cells1 , 2006, The Journal of Immunology.

[163]  Jiaoti Huang,et al.  Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer* , 2006, Journal of Biological Chemistry.

[164]  T. Vomastek,et al.  Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. , 2006, Cancer research.

[165]  David C. Corney,et al.  Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. , 2006, Cancer research.

[166]  Anna Frolov,et al.  Targeting Aurora kinases for the treatment of prostate cancer. , 2006, Cancer research.

[167]  S. Batra,et al.  Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. , 2006, Endocrine-related cancer.

[168]  C. Simbulan-Rosenthal,et al.  PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase , 2003, Oncogene.

[169]  S. Parsons,et al.  Interleukin-6- and Cyclic AMP-Mediated Signaling Potentiates Neuroendocrine Differentiation of LNCaP Prostate Tumor Cells , 2001, Molecular and Cellular Biology.

[170]  L. Dogliotti,et al.  Circulating neuroendocrine markers in patients with prostate carcinoma , 2000, Cancer.

[171]  T. Chung,et al.  STAT3 mediates IL‐6‐induced neuroendocrine differentiation in prostate cancer cells , 2000, The Prostate.

[172]  J Isola,et al.  Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. , 1997, Cancer research.

[173]  Daniel Metzger,et al.  Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase , 1995, Science.

[174]  Jiaoti Huang,et al.  Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer. , 2019, Cancer letters.

[175]  M. Rubin,et al.  The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer. , 2017, Cancer discovery.

[176]  C. Collins,et al.  SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition. , 2017, European urology.

[177]  H. Beltran,et al.  Personalizing Therapy for Metastatic Prostate Cancer: The Role of Solid and Liquid Tumor Biopsies. , 2017, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[178]  F. Saad,et al.  Enzalutamide in Metastatic Prostate Cancer before Chemotherapy , 2014 .