Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer

Abstract

Background: Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization.

GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells

“…GRK3 and NE marker ENO2 are up-regulated as the LNCaP cells become androgen-independent after long term ADT (Supplementary Figure S2). To mimic castration-induced neuroendocrine differentiation in vivo , we compared the expression of GRK3 and NE markers between untreated PAC prostate cancer patient-deprived xenograft (PDX) LTL331 and NEPC PDX LTL331R that was derived from LTL331 after relapse from castration [14, 32, 33, 53]. GRK3 and NE markers (ENO2, CHGA and CHGB) are significantly up-regulated in LTL331R (Figure 2C).…”

“…NEPC is associated with aggressive disease, frequent metastases to soft tissues and a short survival time [5–9]. With the recent introduction of potent ADT drugs, such as enzalutamide and abiraterone acetate, the incidence of NEPC is expected to increase dramatically [1, 2, 10–14]. A better understanding of the molecular events underlying NEPC development is urgently needed to develop a therapeutic solution for CRPC/NEPC.…”

“…The majority of evidence to date favor a transdifferentiation model of NEPC origin, where PAC treated extensively with androgen deprivation therapy (ADT) or radiation therapy develop into NEPC, as a mechanism of adaptive response and drug resistance [8, 9, 16–31]. Recently, neuroendocrine differentiation (NED) has been observed in a patient-derived xenograft model of prostate adenocarcinomas that developed NEPC after medical castration [14, 32, 33]. Many NED-inducing stimuli (such as androgen depletion and irradiation) act through increasing the intracellular level of cAMP that activates protein kinase A (PKA), which in turn activates CREB (cAMP response element-binding protein) via phosphorylation at S133 [15, 21, 23, 24, 28, 34–36].…”

Present and Future of Personalized Medicine in Adult Genitourinary Tumors

“…However, Whyatt et al have recently showed that the multitude of rare genomic and transcriptomic alterations observed in a high-risk tumors seems to converge on a limited number of key pathways [9], thus preserving the rational for future personalized strategies in PCa patients.…”

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“…The rate of killing elicited by targeted agents is too slow, allowing the tumors to adapt to the therapy [8][9][10]. Additionally, tumors are heterogeneous and possess a number of different subpopulations [11][12][13]. Targeted therapies are directed at specific subpopulations, and therefore cannot be expected to eradicate the entire tumor.…”