title: Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.
abstract: Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.
authors.affiliation: Translational Research Department, Institut Curie, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Guyader
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Céraline
authors.forename: Eléonore
authors.initials: E
authors.lastname: Gravier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Morin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Michel
authors.forename: Eva
authors.initials: E
authors.lastname: Erdmann
authors.forename: Gonzague
authors.initials: G
authors.lastname: de Pinieux
authors.forename: Florence
authors.initials: F
authors.lastname: Cabon
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bergerat
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
mesh_terms: D000728:Androgens / Q000172:deficiency / Q000627:therapeutic use*; D000818:Animals; D001483:Base Sequence; D002369:Castration; D016000:Cluster Analysis; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C508053:ERBB2 protein, human