Table 1.

Targeted therapies in NEPC.

Ref.	Molecular alteration	Pathway/process	Target	Agent	Result
(10, 62)	TP53 mutation	IL8-CXCR2-p53	p53–Mdm2	SAR405838	Tumor regression in LNCaP mouse model, Ph1 ongoing
(12, 63)	RB1 deletion	RB–E2F1–Mad2	Spindle disruption	Paclitaxel, STLC	Prolonged mitotic and increased cell death in PC3, DU145 cells
(14, 51, 52)	PLK1 upregulation	AURKA–PLK1–Cdc25	PLK1	BI 2536, BI 6727	Decreased proliferation and clonogenic potential of DU145, LNCaP, PC3 cells Ph1:limited toxicity and efficacy in solid tumors, Ph2 ongoing
(15, 16, 46)	AURKA, MYCN amplification	MYCN–AURKA–pH3-SYP/NSE	AURKA	Danusertib, alisertib	Ph2: 13.6% SD ≥6 mos CRPC
(17, 64, 65)	c-MYC overexpression	PIM1-c-MYC	c-Myc, PIM1	10058-F4, Quercetagetin	Reduced tumorigenic potentials of LNCaP and DU145 and reduced Pim1 protein, increased synaptophysin and Ascl1 in human PC tumors with coexpression of PIM1-c-MYC, growth inhibition of RWPE2 PC cells
(21, 22)	PCDH-PC overexpression	Wnt	PCDH-PC	PCDH-PC si-RNA	Blocked NE differentiation of LNCaP, sensitized human CRPC tumors to docetaxel
(25)	EZH2 overexpression	IFN–JAK–STAT1	EZH2	DZNep	Pharmacologic depletion of EZH2 by the histone-methylation inhibitor DZNep and synergistic antitumor effect with IFN-γ in DU145 cells
(66)	IL-6 overexpression	PEDF–NFκB–STAT3	IL-6, STAT3	Siltuximab, LLL12	Suppressed clonogenicity of stem-like cells in patients with high-grade disease and derived murine xenograft model
(29, 67)	MIF overexpression	AKT/ERK	MIF	ISO-1	Decreased tumor volume and angiogenesis in DU145 xenografts
(30, 68)	FAK overactivation	Integrin-FAK	FAK	PF-562,271, PF-00562271	Attenuation of FAK and AKT phosphorylation and abrogation of docetaxel-resistance of DU145-Rx and PC3-Rx cells, TRAMP mice
(31)	Siah2 overexpression	HIF-1α-FoxA2-Hes6/Sox9/Jmjd1a	Siah2	Menadione	Cell death by autoschizis in DU145 cells
(33, 34, 50, 69–74)	c-Kit amplification	MMP-9–SCF-c-Kit	c-Kit	Imatinib, dasatinib, sunitinib, sorafenib, masitinib, cabozantinib	Ph1imatinib: high incidence of thromboembolic events with docetaxel/estramustine combination for CRPC. Ph2 imatinib: limited PSA response, toxicities in biochemical failure patients Ph3 dasatinib: addition of dasatinib to docetaxel did not improve overall survival in mCRPC. Ph3 sunitinib: plus prednisone did not improve OS compared with prednisone alone in docetaxel-refractory mCRPC Ph2 sorafenib: 20% PR mTTP 5.9 mos, mOS 14.6 mos. Ph2 cabozantinib: improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers, mOS 10.8 mos
(35, 36, 75)	Snail overexpression	NFκB–Snail–RKIP-NSE/CgA	Snail	Salinosporamide A, flavonoids, parthenolide	Inhibition of antiapoptotic gene products and chemoimmunosensitization of DU145 cells
(37)	Adrenomedullin overexpression	CRLR–RAMP2,3–NSE	Adrenomedullin	KT-5823	Inhibition of neurite outgrowth in LNCaP cells
(38, 40)	Src overexpression	PTHrP-AR	Src	Dasatinib	Ph3: addition of dasatinib to docetaxel did not improve overall survival in mCRPC
(42)	RANKL overexpression	RANKL-RANK-c-Met-AR	RANKL	Denosumab	Ph3: delayed time to first bone metastasis vs. placebo in CRPC (33.2 mos)
(43)	RAS amplification	RAS–ERK1/2	RAS	Zolendronic acid	Apoptosis and inhibition of proliferation and migration in NE allograft (NE-10) and its cell line (NE-CS), which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse.
(45)	Host-cancer immunological interactions	Cellular immunity	PAP-GM-CSF	Sipuleucel-T	Ph3: sipuleucel-T prolonged overall survival (25.8 mos) vs. placebo (21.7) in mCRPC
(54, 55)	Met overexpression	HGF/Met	Met	Cabozantinib, BMS-777607	Ph2 cabozantinib: improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers, mOS 10.8 mos. Suppressed cell migration and invasion of PC3 and DU145 cells
(56)	AKT overactivation	PI3K/AKT/mTOR	AKT	MK-2206	Ph1: 1 PR in NEPC