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 Medina; Robert C. Doebele; William A. Robinson

doi:10.1158/1535-7163.MCT-17-0472

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

Department of Computer Science and Engineering

Research output: Contribution to journal › Article › peer-review

36 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 (ALK ^ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ^ATI 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 ALK ^ATI 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 ALK ^ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ^ATI 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 ALK ^ATI 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 ALK ^ATI .

Original language	English
Pages (from-to)	222-231
Number of pages	10
Journal	Molecular cancer therapeutics
Volume	17
Issue number	1
DOIs	https://doi.org/10.1158/1535-7163.MCT-17-0472
Publication status	Published - 2018 Jan

Bibliographical note

Funding Information:
We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation.

Funding Information:
We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation. This work was supported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934).

Funding Information:
This work wassupported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934).

Publisher Copyright:
© 2017 American Association for Cancer Research.

ASJC Scopus subject areas

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1535-7163.MCT-17-0472

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Couts, K. L., Bemis, J., Turner, J. A., Bagby, S. M., Murphy, D., Christiansen, J., Hintzsche, J. D., Le, A., Pitts, T. M., Wells, K., Applegate, A., Amato, C., Multani, P., Chow-Maneval, E., Tentler, J. J., Shellman, Y. G., Rioth, M. J., Tan, A. C., Gonzalez, R., ... 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

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, AC, 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

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title = "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 (ALK ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ATI 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 ALK ATI 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 ALK ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ATI 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 ALK ATI 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 ALK ATI .",

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

note = "Funding Information: We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation. Funding Information: We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation. This work was supported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934). Funding Information: This work wassupported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934). Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

year = "2018",

month = jan,

doi = "10.1158/1535-7163.MCT-17-0472",

language = "English",

volume = "17",

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journal = "Molecular cancer therapeutics",

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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.

N1 - Funding Information: We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation. Funding Information: We thank the patient and her family for her clinical trial participation and previous patients at the University of Colorado Hospital for donating tumor tissue used in this study. We also thank the clinical trial staff at the University of Colorado, the University of Colorado Denver Genomics and Microarray Core, and the University of Colorado Cancer Center (UCCC) Molecular Pathology Shared Resource for cytogenetic analysis. This work was funded in part by the Paul R. Ohara II Seed Grant Program, an American Cancer Society Institutional Research Grant to University of Colorado Cancer Center, the Amy Davis Foundation, and the Moore Family Foundation. This work was supported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934). Funding Information: This work wassupported in part by the NIH/NCATS Colorado CTSA Grant (UL1 TR001082) and the NIH/NCI Cancer Center Support Grant (P30CA046934). Publisher Copyright: © 2017 American Association for Cancer Research.

PY - 2018/1

Y1 - 2018/1

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 (ALK ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ATI 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 ALK ATI 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 ALK ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ATI 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 ALK ATI 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 ALK ATI .

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 (ALK ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ATI 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 ALK ATI 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 ALK ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ATI 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 ALK ATI 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 ALK ATI .

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DO - 10.1158/1535-7163.MCT-17-0472

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JO - Molecular cancer therapeutics

JF - Molecular cancer therapeutics

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ER -

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

Abstract

Bibliographical note

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UN SDGs

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