Anaplastic Lymphoma Kinase Mutation ( ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib

Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase ( ) 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 SCCP with F1174C-activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in gene, mRNA, and its impact in clinical outcomes. 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. NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified 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 amplification was associated with poor outcome. In prostate cancer cells and organoids, F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting F1174C-expressing cell growth. These findings implicate -activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting molecular alterations in some patients with SCCP. .