Reference Detail

Ref Type

Journal Article

PMID

(29559559)

Authors

Carneiro BA, Pamarthy S, Shah AN, Sagar V, Unno K, Han H, Yang XJ, Costa RB, Nagy RJ, Lanman RB, Kuzel TM, Ross JS, Gay L, Elvin JA, Ali SM, Cristofanilli M, Chae YK, Giles FJ, Abdulkadir SA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	12	2018 Jun 15	2732-2739	Clin Cancer Res

URL

Abstract Text

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. Clin Cancer Res; 24(12); 2732-9. ©2018 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	F1174C	missense	gain of function	ALK F1174C lies within the protein kinase domain of the Alk protein (UniProt.org). F1174C confers a gain of function to Alk, as indicated by constitutive Alk phosphorylation (PMID: 24509625), and increased cell viability in culture (PMID: 29559559).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK F1174C	prostate small cell carcinoma	predicted - sensitive	Alectinib	Case Reports/Case Series	Actionable	In a clinical case report, Alecensa (alectinib) treatment in a patient with prostate small cell carcinoma harboring ALK F1174C resulted in stable disease and a decrease in ALK F1174C allele fraction in circulating tumor DNA, with clinical benefit ongoing after 7 months (PMID: 29559559).	29559559