Data from Anaplastic Lymphoma Kinase Mutation (<i>ALK</i> F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib

Abstract

<div>Abstract<p><b>Purpose:</b> Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise <i>de novo</i> or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (<i>ALK</i>) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory <i>de novo</i> SCCP with <i>ALK</i> F1174C–activating mutation who obtained clinical benefit from treatment with ALK inhibitor.</p><p><b>Experimental Design:</b> Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in <i>ALK</i> gene, mRNA, and its impact in clinical outcomes. <i>In vitro</i> prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib.</p><p><b>Results:</b> NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified <i>ALK</i> F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that <i>ALK</i> amplification was associated with poor outcome. In prostate cancer cells and organoids, <i>ALK</i> F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting <i>ALK</i> F1174C–expressing cell growth.</p><p><b>Conclusions:</b> These findings implicate <i>ALK</i>-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting <i>ALK</i> molecular alterations in some patients with SCCP. <i>Clin Cancer Res; 24(12); 2732–9. ©2018 AACR</i>.</p></div>