Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched in PI3K-Akt, mTOR, and MAPK signaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC. In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice.
AkamatsuS., WyattA.W., LinD., LysakowskiS., ZhangF., KimS., et al. (2015). The placental gene PEG10 promotes progression of neuroendocrine prostate cancer. Cell Rep, 12, 922–936.
3.
AparicioA.M., HarzstarkA.L., CornP.G., WenS., AraujoJ.C., TuS.M., et al. (2013). Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res, 19, 3621–3630.
4.
BarrettD., BrownV.I., GruppS.A., and TeacheyD.T. (2012). Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs, 14, 299–316.
5.
BeltranH., JendrisakA., LandersM., MosqueraJ.M., KossaiM., LouwJ., et al. (2016a). The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clin Cancer Res, 22, 1510–1519.
BeltranH., TomlinsS., AparicioA., AroraV., RickmanD., AyalaG., et al. (2014). Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res, 20, 2846–2850.
9.
BodenmillerB., WankaS., KraftC., UrbanJ., CampbellD., PedrioliP.G., et al. (2010). Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast. Science Signal, 3, rs4.
10.
ChenR., DongX., and GleaveM. (2018). Molecular model for neuroendocrine prostate cancer progression. BJU Int [Epub ahead of print]; DOI: 10.1111/bju.14207.
11.
CohenP. (2002). Protein kinases—the major drug targets of the twenty-first century?. Nat Rev Drug Discov, 1, 309–315.
12.
DardenneE., BeltranH., BenelliM., GayvertK., BergerA., PucaL., et al. (2016). N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell, 30, 563–577.
13.
DrakeJ.M., PaullE.O., GrahamN.A., LeeJ.K., SmithB.A., TitzB., et al. (2016). Phosphoproteome integration reveals patient-specific networks in prostate cancer. Cell, 166, 1041–1054.
14.
DubrovskaA., KimS., SalamoneR.J., WalkerJ.R., MairaS.M., Garcia-EcheverriaC., et al. (2009). The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A, 106, 268–273.
15.
EllisL., and LodaM. (2015). Advanced neuroendocrine prostate tumors regress to stemness. Proc Natl Acad Sci U S A, 112, 14406–14407.
16.
GreenhalghJ., BagustA., BolandA., DwanK., BealeS., HockenhullJ., et al. (2015). Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation. Health Technol Assessment (Winchester, England), 19, 1–134.
17.
GuoC.C., DancerJ.Y., WangY., AparicioA., NavoneN.M., TroncosoP., et al. (2011). TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Hum Pathol, 42, 11–17.
18.
HunterT. (2009). Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol, 21, 140–146.
19.
HuttlinE.L., JedrychowskiM.P., EliasJ.E., GoswamiT., RadR., BeausoleilS.A., et al. (2010). A tissue-specific atlas of mouse protein phosphorylation and expression. Cell, 143, 1174–1189.
20.
IesmantaviciusV., WeinertB.T., and ChoudharyC. (2014). Convergence of ubiquitylation and phosphorylation signaling in rapamycin-treated yeast cells. Mol Cell Proteomics, 13, 1979–1992.
21.
KaushikA.K., and SreekumarA. (2016). Genomic aberrations drive clonal evolution of neuroendocrine tumors. Trends Endocrinol Metab TEM, 27, 242–244.
22.
KimJ., JinH., ZhaoJ.C., YangY.A., LiY., YangX., et al. (2017). FOXA1 inhibits prostate cancer neuroendocrine differentiation. Oncogene, 36, 4072–4080.
23.
KimJ.K., JungY., WangJ., JosephJ., MishraA., HillE.E., et al. (2013). TBK1 regulates prostate cancer dormancy through mTOR inhibition. Neoplasia (New York, NY), 15, 1064–1074.
24.
KuS.Y., RosarioS., WangY., MuP., SeshadriM., GoodrichZ.W., et al. (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science (New York, NY), 355, 78–83.
25.
LeeS.H., JohnsonD., LuongR., and SunZ. (2015). Crosstalking between androgen and PI3K/AKT signaling pathways in prostate cancer cells. J Biol Chem, 290, 2759–2768.
26.
LotanT.L., GuptaN.S., WangW., ToubajiA., HaffnerM.C., ChauxA., et al. (2011). ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol, 24, 820–828.
27.
ManningG., WhyteD.B., MartinezR., HunterT., and SudarsanamS. (2002). The protein kinase complement of the human genome. Science (New York, NY), 298, 1912–1934.
28.
MarholdM., TomasichE., El-GazzarA., HellerG., SpittlerA., HorvatR., et al. (2015). HIF1alpha regulates mTOR signaling and viability of prostate cancer stem cells. Mol Cancer Res, 13, 556–564.
29.
MarquesR.B., AghaiA., de RidderC.M.A., StuurmanD., HoebenS., BoerA., et al. (2015). High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur Urol, 67, 1177–1185.
30.
MateoF., ArenasE.J., AguilarH., Serra-MusachJ., de GaribayG.R., BoniJ., et al. (2017). Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene, 36, 2737–2749.
31.
MuP., ZhangZ., BenelliM., KarthausW.R., HooverE., ChenC.C., et al. (2017). SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science, 355, 84–88.
32.
MulhollandD.J., KobayashiN., RuscettiM., ZhiA., TranL.M., HuangJ., et al. (2012). Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res, 72, 1878–1889.
33.
NadalR., SchweizerM., KryvenkoO.N., EpsteinJ.I., and EisenbergerM.A. (2014). Small cell carcinoma of the prostate. Nat Rev Urol, 11, 213–219.
34.
O'BrianC.A. (1998). Protein kinase C-alpha: a novel target for the therapy of androgen-independent prostate cancer? (Review-hypothesis). Oncol Rep, 5, 305–309.
35.
PezaroC., OmlinA., LorenteD., RodriguesD.N., FerraldeschiR., BianchiniD., et al. (2014). Visceral disease in castration-resistant prostate cancer. Eur Urol, 65, 270–273.
36.
PolivkaJ.Jr., and JankuF. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther, 142, 164–175.
37.
Rodriguez-MorenoJ.F., Apellaniz-RuizM., Roldan-RomeroJ.M., DuranI., BeltranL., Montero-CondeC., et al. (2017). Exceptional response to temsirolimus in a metastatic clear cell renal cell carcinoma with an early novel MTOR-activating mutation. J Natl Compr Canc Netw, 15, 1310–1315.
38.
RoskoskiR.Jr. (2015). A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res, 100, 1–23.
39.
SharmaK., D'SouzaR.C., TyanovaS., SchaabC., WisniewskiJ.R., CoxJ., et al. (2014). Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep, 8, 1583–1594.
40.
SiegelR.L., MillerK.D., and JemalA. (2016). Cancer statistics, 2016. CA Cancer J Clin, 66, 7–30.
41.
SmithB.A., SokolovA., UzunangelovV., BaertschR., NewtonY., GraimK., et al. (2015). A basal stem cell signature identifies aggressive prostate cancer phenotypes. Proc Natl Acad Sci U S A, 112, E6544–E6552.
42.
WangH.T., YaoY.H., LiB.G., TangY., ChangJ.W., and ZhangJ. (2014). Neuroendocrine prostate cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. J Clin Oncol, 32, 3383–3390.
43.
ZaffutoE., PompeR., ZanatyM., BondarenkoH.D., Leyh-BannurahS.R., MoschiniM., et al. (2017). Contemporary incidence and cancer control outcomes of primary neuroendocrine prostate cancer: a SEER database analysis. Clin Genitourin Cancer, 15, e793–e800.
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