ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms

Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D. Hintzsche, Anh Le, Todd M. Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa MedinaRobert C. Doebele, William A. Robinson

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 patientderived 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 ALKATI.

Original languageEnglish
Pages (from-to)222-231
Number of pages10
JournalMolecular Cancer Therapeutics
Volume17
Issue number1
DOIs
Publication statusPublished - 2018 Jan 1
Externally publishedYes

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Melanoma
Protein Isoforms
Therapeutics
Heterografts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Couts, K. L., Bemis, J., Turner, J. A., Bagby, S. M., Murphy, D., Christiansen, J., ... Robinson, W. A. (2018). ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms. Molecular Cancer Therapeutics, 17(1), 222-231. https://doi.org/10.1158/1535-7163.MCT-17-0472

ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms. / Couts, Kasey L.; Bemis, Judson; Turner, Jacqueline A.; Bagby, Stacey M.; Murphy, Danielle; Christiansen, Jason; Hintzsche, Jennifer D.; Le, Anh; Pitts, Todd M.; Wells, Keith; Applegate, Allison; Amato, Carol; Multani, Pratik; Chow-Maneval, Edna; Tentler, John J.; Shellman, Yiqun G.; Rioth, Matthew J.; Tan, Aik-Choon; Gonzalez, Rene; Medina, Theresa; Doebele, Robert C.; Robinson, William A.

In: Molecular Cancer Therapeutics, Vol. 17, No. 1, 01.01.2018, p. 222-231.

Research output: Contribution to journalArticle

Couts, KL, Bemis, J, Turner, JA, Bagby, SM, Murphy, D, Christiansen, J, Hintzsche, JD, Le, A, Pitts, TM, Wells, K, Applegate, A, Amato, C, Multani, P, Chow-Maneval, E, Tentler, JJ, Shellman, YG, Rioth, MJ, Tan, A-C, Gonzalez, R, Medina, T, Doebele, RC & Robinson, WA 2018, 'ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms', Molecular Cancer Therapeutics, vol. 17, no. 1, pp. 222-231. https://doi.org/10.1158/1535-7163.MCT-17-0472
Couts, Kasey L. ; Bemis, Judson ; Turner, Jacqueline A. ; Bagby, Stacey M. ; Murphy, Danielle ; Christiansen, Jason ; Hintzsche, Jennifer D. ; Le, Anh ; Pitts, Todd M. ; Wells, Keith ; Applegate, Allison ; Amato, Carol ; Multani, Pratik ; Chow-Maneval, Edna ; Tentler, John J. ; Shellman, Yiqun G. ; Rioth, Matthew J. ; Tan, Aik-Choon ; Gonzalez, Rene ; Medina, Theresa ; Doebele, Robert C. ; Robinson, William A. / ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 1. pp. 222-231.
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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 patientderived 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 ALKATI.",
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T1 - ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms

AU - Couts, Kasey L.

AU - Bemis, Judson

AU - Turner, Jacqueline A.

AU - Bagby, Stacey M.

AU - Murphy, Danielle

AU - Christiansen, Jason

AU - Hintzsche, Jennifer D.

AU - Le, Anh

AU - Pitts, Todd M.

AU - Wells, Keith

AU - Applegate, Allison

AU - Amato, Carol

AU - Multani, Pratik

AU - Chow-Maneval, Edna

AU - Tentler, John J.

AU - Shellman, Yiqun G.

AU - Rioth, Matthew J.

AU - Tan, Aik-Choon

AU - Gonzalez, Rene

AU - Medina, Theresa

AU - Doebele, Robert C.

AU - Robinson, William A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 patientderived 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 ALKATI.

AB - 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 patientderived 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 ALKATI.

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