Roubaud Guilhem, Liaw Bobby C, Oh William K, Mulholland David J
Department of Medical Oncology, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux 33076, France.
Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, 1470 Madison Avenue, New York, New York 10029, USA.
Nat Rev Clin Oncol. 2017 May;14(5):269-283. doi: 10.1038/nrclinonc.2016.181. Epub 2016 Nov 22.
The increasing potency of therapies that target the androgen receptor (AR) signalling axis has correlated with a rise in the proportion of patients with prostate cancer harbouring an adaptive phenotype, termed treatment-induced lineage crisis. This phenotype is characterized by features that include soft-tissue metastasis and/or resistance to standard anticancer therapies. Potent anticancer treatments might force cancer cells to evolve and develop alternative cell lineages that are resistant to primary therapies, a mechanism similar to the generation of multidrug- resistant microorganisms after continued antibiotic use. Herein, we assess the hypothesis that treatment-adapted phenotypes harbour reduced AR expression and/or activity, and acquire compensatory strategies for cell survival. We highlight the striking similarities between castration-resistant prostate cancer and triple-negative breast cancer, another poorly differentiated endocrine malignancy. Alternative treatment paradigms are needed to avoid therapy-induced resistance. Herein, we present a new clinical trial strategy designed to evaluate the potential of rapid drug cycling as an approach to delay the onset of resistance and treatment-induced lineage crisis in patients with metastatic castration-resistant prostate cancer.
靶向雄激素受体（AR）信号轴的治疗方法效力不断增强，这与前列腺癌患者中具有适应性表型（称为治疗诱导的谱系危机）的比例上升相关。这种表型的特征包括软组织转移和/或对标准抗癌疗法的耐药性。强效抗癌治疗可能会迫使癌细胞进化并发展出对一线治疗耐药的替代细胞谱系，这一机制类似于持续使用抗生素后产生多重耐药微生物的过程。在此，我们评估这样一种假说：适应治疗的表型中AR表达和/或活性降低，并获得了细胞存活的补偿策略。我们强调去势抵抗性前列腺癌与三阴性乳腺癌（另一种低分化内分泌恶性肿瘤）之间的显著相似性。需要采用替代治疗模式来避免治疗诱导的耐药性。在此，我们提出一种新的临床试验策略，旨在评估快速药物循环作为一种延缓转移性去势抵抗性前列腺癌患者耐药性发作和治疗诱导的谱系危机的方法的潜力。
