Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer

Sittadjody, Sivanandane; Thangasamy, Thilakavathy; NickKolgh, Bita; Balaji, K.C.

doi:10.1007/978-3-319-31341-2_4

Cited by 2 publications

(5 citation statements)

References 181 publications

(183 reference statements)

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“…7 and Additional file 1 : Table S6), supporting the hypothesis of their involvement in drug resistance. Androgen-resistant cell survival was supported by the activation of the two signaling pathways AKT and p38MAPK, in agreement with studies on tissues from CRPC patients [ 2 , 3 , 33 ]. The roles of PARP-1 in genome maintenance and transcriptional regulation during PCa progression have been reported [ 14 , 36 ].…”

Section: Discussionsupporting

confidence: 88%

“…Studies on CRPC tissues showed that genomic and transcriptomic changes also involved non-androgen pathways of which the most important are PI3K/AKT, RAF/MAPK/ERK and DNA repair [ 2 , 32 , 33 ]. LNCaP, PDB and MDB cell lysates were assessed for total and phosphorylated AKT and p38MAPK.…”

Section: Resultsmentioning

confidence: 99%

“…The ‘omic’ technologies have delineated a highly heterogeneous landscape of molecular alterations in CRPC tissues that may influence patient prognosis and response to therapy [ 5 , 33 , 41 ]. While most CRPC still maintain AR-mediated signaling activity, AR-independent pathways are also involved in resistance to ADT, decreasing androgen receptor signaling inhibitors treatment effectiveness [ 2 – 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, the molecular mechanisms by which hormone-sensitive PCa cells acquire the ability to resist to hormone deprivation remain largely unknown, thus preventing the development of effective therapies. AR reactivation has been shown to occur in many CRPC cell populations and, at the same time, AR-independent signaling pathways may be activated evading canonical cell growth control strategies [ 2 – 4 ]. During PCa evolution and progression, cell heterogeneity is generated by genomic rearrangements and rare mutations converging on specific biological processes and pathways [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

et al. 2017

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BackgroundProstate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges.MethodsWestern blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution.ResultsTreating the androgen-responsive LNCaP cell line for over a year with 10 μM bicalutamide both in the presence and absence of 0.1 nM 5-α-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression.ConclusionsOur models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.Electronic supplementary materialThe online version of this article (10.1186/s12964-017-0206-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

et al. 2017

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“…Also, the lowest dosage of ipatasertib (200 mg) in combination with abiraterone determined a rPFS advantage in patients with PTEN loss compared to those without PTEN alterations (rPFS: 11.1 vs 4.6 months HR:0.46 [0.22-0.70] p = 0.028). When PTEN is deleted, AKT regulates PC cells proliferation, while AR regulates their survival, thus offering a possible explanation of these results and supporting the rationale of combining AKT blockers with AR modulators (Sittadjody et al, 2016). This notion has guided a phase I (Meyer et al, 2014) dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 in heavily pretreated patients with mCRPC (Kolinsky et al, 2017).…”

Section: Pi3k-akt-mtor Pathwaymentioning

confidence: 87%

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Cattrini

Zanardi

Vallome

et al. 2017

Critical Reviews in Oncology/Hematology

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Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.

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Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer

Cited by 2 publications

References 181 publications

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

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