Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib

Benedito A. Carneiro*, Sahithi Pamarthy, Ami N. Shah, Vinay Sagar, Kenji Unno, Hui Ying Han, Ximing J. Yang, Rubens B. Costa, Rebecca J. Nagy, Richard B. Lanman, Timothy M. Kuzel, Jeffrey S. Ross, Laurie Gay, Julia A. Elvin, Siraj M. Ali, Massimo Cristofanilli, Young K. Chae, Francis J. Giles, Sarki A. Abdulkadir

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)2732-2739
Number of pages8
JournalClinical Cancer Research
Issue number12
StatePublished - Jun 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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