title: [Hormone Resistance and Neuroendocrine Differentiation Due to Accumulation of Genetic Lesions during Clonal Evolution of Prostate Cancer].
abstract: Progression of malignant tumors is largely due to clonal evolution of the primary tumor, clones acquiring different sets of molecular genetic lesions. Lesions can confer a selective advantage in proliferation rate or metastasis on the tumor cell population, especially if developing resistance to anticancer therapy. Prostate cancer (PCa) provides an illustrative example of clinically significant clonal evolution. The review considers the genetic alterations that occur in primary PCa and the mechanism whereby hormone-refractory PCa develops on hormone therapy, including mutations and alternative splicing of the androgen receptor gene (AR) and intratumoral androgen synthesis. Certain molecular genetic lesions determine resistance to new generation inhibitors (AR mutations that block the antagonist effect or allow other hormones to activate the receptor) or lead to neuroendocrine differentiation (repression of the AR signaling pathway, TP53 mutations, and amplification of the AURKA or MYCN oncogene). Multistep therapy based on the data about somatic mutations associated with progression and metastasis of the primary tumor can be expected to significantly improve the survival of patients with advanced PCa in the nearest future.
authors.affiliation: Lopatkin Institute of Urology and Interventional Radiology, National Medical Radiological Research Center, Ministry of Health, Moscow, 105425 Russia.|Research Centre for Medical Genetics, Moscow, 115478 Russia.|dimserg@mail.ru.
authors.forename: D S
authors.initials: DS
authors.lastname: Mikhaylenko
authors.affiliation: Lopatkin Institute of Urology and Interventional Radiology, National Medical Radiological Research Center, Ministry of Health, Moscow, 105425 Russia.
authors.forename: G D
authors.initials: GD
authors.lastname: Efremov
authors.affiliation: Lopatkin Institute of Urology and Interventional Radiology, National Medical Radiological Research Center, Ministry of Health, Moscow, 105425 Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Sivkov
authors.affiliation: Research Centre for Medical Genetics, Moscow, 115478 Russia.|Sechenov First Moscow State Medical University, Moscow, 119991 Russia.
authors.forename: D V
authors.initials: DV
authors.lastname: Zaletaev
mesh_terms: D017398:Alternative Splicing; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D060965:Clonal Evolution / Q000187:drug effects / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D011944:Receptors, Androgen
keywords: clonal evolution; hormone-refractory tumor; neuroendocrine differentiation; oncogene; prostate cancer; somatic mutation; targeted therapy