Resistance to Hormonal Therapy in Prostate Cancer
Several therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype.
Progression to ADT leads to the attainment of a castration resistant disease whose mechanisms remain incompletely understood. Reactivation of AR has been shown to occur and second-generation of AR targeting drugs are usually prescribed. Upon progression to these agents AR signaling still remains the primary driver although it often becomes ligand independent, since it can be either restored through mutations on the ligand binding domain and/or formation of AR splicing variants or by passed through a cross talk with other oncogenic signaling pathways.
AR-independent signaling pathways may represent additional mechanisms underlying castration resistant progression. It is clear that castration resistant prostate cancer is a group of diverse diseases and new treatment paradigms need to be developed.
KeywordsAndrogen receptor splice variant Castration resistant prostate cancer Endocrine therapy resistance
- Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, van der Poel HG, van der Kwast TH, Rouvière O, Wiegel T, Mottet N (2017) Eau-estro-siog guidelines on prostate cancer. Part II: Treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 71(4):630–642. doi: 10.1016/j.eururo.2016.08.002 PubMedCrossRefGoogle Scholar
- Steinestel J, Luedeke M, Arndt A, Schnoeller TJ, Lennerz JK, Wurm C, Maier C, Cronauer MV, Steinestel K, Schrader AJ, Steinestel J, Luedeke M, Arndt A, Schnoeller TJ, Lennerz JK, Wurm C, Maier C, Cronauer MV, Steinestel K, Schrader AJ (2015) Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget. doi: 10.18632/oncotarget.3925 PubMedPubMedCentralCrossRefGoogle Scholar
- Steketee K, Timmerman L, Ziel-Van Der Made AC, Doesburg P, Brinkmann AO, Trapman J (2002) Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of h874 and mutation hot spot t877 in prostate cancer. Int J Cancer 100(3):309–317PubMedCrossRefGoogle Scholar
- Taplin ME, Montgomery B, Logothetis CJ et al (2014) Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase ii neoadjuvant study. J Clin Oncol 32(33):3705–3715PubMedPubMedCentralCrossRefGoogle Scholar
- Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E (1992) Anti-androgens and the mutated androgen receptor of lncap cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation. Biochemistry 31(8):2393–2399PubMedCrossRefGoogle Scholar
- Wang HT, Yao YH, Li BG, Tang Y, Chang JW, Zhang J (2014) Neuroendocrine prostate cancer (nepc) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of nepc and survival from nepc diagnosis-a systematic review and pooled analysis. J Clin Oncol 32(30):3383–3390PubMedCrossRefGoogle Scholar