title: Androgen deprivation induces phenotypic plasticity and promotes resistance to molecular targeted therapy in a PTEN-deficient mouse model of prostate cancer.
abstract: Castration-resistant prostate cancer is an incurable heterogeneous disease that is characterized by a complex multistep process involving different cellular and biochemical changes brought on by genetic and epigenetic alterations. These changes lead to the activation or overexpression of key survival pathways that also serve as potential therapeutic targets. Despite promising preclinical results, molecular targeted therapies aimed at such signaling pathways have so far been dismal. In the present study, we used a PTEN-deficient mouse model of prostate cancer to show that plasticity in castration-resistant tumors promotes therapeutic escape. Unlike castration-naïve tumors which depend on androgen receptor and PI3K/AKT signal activation for growth and survival, castration-resistant tumors undergo phenotypic plasticity leading to increased intratumoral heterogeneity. These tumors attain highly heterogeneous phenotypes that are characterized by cancer cells relying on alternate signal transduction pathways for growth and survival, such as mitogen-activated protein kinase and janus kinase/signal transducer and activator of transcription, and losing their dependence on PI3K signaling. These features thus enabled castration-resistant tumors to become insensitive to the therapeutic effects of PI3K/AKT targeted therapy. Overall, our findings provide evidence that androgen deprivation drives phenotypic plasticity in prostate cancer cells and implicate it as a crucial contributor to therapeutic resistance in castration-resistant prostate cancer. Therefore, incorporating intratumoral heterogeneity in a dynamic tumor model as a part of preclinical efficacy determination could improve prediction for response and provide better rationale for the development of more effective therapies.
authors.affiliation: Department of Urology and Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan, mdev@med.kindai.ac.jp.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Department of Urology, Iga City General Hospital, Iga, Mie 518-0823, Japan and.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Urology and.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Urology and.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Urology and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Promoting Center for Clinical Research, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Urology and.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002070:Butadienes / Q000008:administration & dosage; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000008:administration & dosage; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D002070:Butadienes; D009570:Nitriles; D011944:Receptors, Androgen; C113580:U 0126; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus