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ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.

ABSTRACT: Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI ) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATIMol Cancer Ther; 17(1); 222-31. ©2017 AACR.

SUBMITTER: Couts KL

PROVIDER: S-EPMC5752582 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.

Couts Kasey L KL Bemis Judson J Turner Jacqueline A JA Bagby Stacey M SM Murphy Danielle D Christiansen Jason J Hintzsche Jennifer D JD Le Anh A Pitts Todd M TM Wells Keith K Applegate Allison A Amato Carol C Multani Pratik P Chow-Maneval Edna E Tentler John J JJ Shellman Yiqun G YG Rioth Matthew J MJ Tan Aik-Choon AC Gonzalez Rene R Medina Theresa T Doebele Robert C RC Robinson William A WA

Molecular cancer therapeutics 20171020 1

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI ) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for A ...[more]

PMID: 29054983

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Project description:Background Pulmonary carcinoids (PC), including typical (TC) and atypical carcinoids (AC), are low-grade neuroendocrine tumors (NETs) which account for 1–5% of all lung tumors. Due to the low prevalence of PC and extreme rarity of anaplastic lymphoma kinase (ALK) rearrangements in patients with PC, the advances in targeted therapy development in PC are still limited and there is no standard treatment. Even though in patients with PC harboring ALK rearrangements there is a room for a success in targeted therapy. To our knowledge, case 1 was the first report to detect ALK gene p.I1171N mutation after taking alectinib and sensitive to ceritinib in patients with atypical carcinoid. Case Description Herein, we report the cases of 2 non-smoking patients, 51 year-old female with tumor in left lower lobe and 49 year-old female with tumor in right upper lobe, both with metastatic PC who harbored EML4-ALK fusion and were sensitive to small-molecule ALK inhibitors. The first patient initially received alectinib, then therapy was switched to ceritinib after developing drug resistance due to the missense mutation of ALK gene p.I1171N mutation in exon 22 detected by next-generation sequencing (NGS), and finally died of intracranial disease progression. The second patient also received alectinib, and her treatment is currently ongoing with good effect and tolerance. After conducting comprehensive review of literature, we found that 14 lung NETs with ALK rearrangements have been reported to date. The clinical outcome was partial response for 6 NETs patients and 5 patients exhibited stable disease after treatment with ALK inhibitors. Conclusions According to the effectiveness of ALK inhibitors in our cases and previous articles, we recommend alectinib for the first-line treatment of metastatic PC with EML4-ALK fusion and highlight the need for molecular profiling of metastatic lung NETs patients and that ALK inhibitors are feasible in the treatment for metastatic lung NETs patients with ALK rearrangements. Finally, further studies to assess the real prevalence of ALK gene fusions and their spectrum of sensitivity to different ALK inhibitors are needed in larger cohorts.

Dataset Information

ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.

Publications

ALK Inhibitor Response in Melanomas Expressing <i>EML4-ALK</i> Fusions and Alternate <i>ALK</i> Isoforms.

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