Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma

Lara Davis, Kevin D. Nusser, Joanna Przybyl, Janet Pittsenbarger, Nicolle E. Hofmann, Sushama Varma, Sujay Vennam, Maria Debiec-Rychter, Matt van de Rijn, Monika Davare

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. Implications: A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.

Original languageEnglish (US)
Pages (from-to)676-685
Number of pages10
JournalMolecular Cancer Research
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Leiomyosarcoma
Phosphotransferases
Sarcoma
Smooth Muscle Myocytes
Neoplasms
RNA Sequence Analysis
Therapeutics
Oncogenes
Survival
Growth
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma. / Davis, Lara; Nusser, Kevin D.; Przybyl, Joanna; Pittsenbarger, Janet; Hofmann, Nicolle E.; Varma, Sushama; Vennam, Sujay; Debiec-Rychter, Maria; van de Rijn, Matt; Davare, Monika.

In: Molecular Cancer Research, Vol. 17, No. 3, 01.03.2019, p. 676-685.

Research output: Contribution to journalArticle

Davis, L, Nusser, KD, Przybyl, J, Pittsenbarger, J, Hofmann, NE, Varma, S, Vennam, S, Debiec-Rychter, M, van de Rijn, M & Davare, M 2019, 'Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma', Molecular Cancer Research, vol. 17, no. 3, pp. 676-685. https://doi.org/10.1158/1541-7786.MCR-18-1075
Davis, Lara ; Nusser, Kevin D. ; Przybyl, Joanna ; Pittsenbarger, Janet ; Hofmann, Nicolle E. ; Varma, Sushama ; Vennam, Sujay ; Debiec-Rychter, Maria ; van de Rijn, Matt ; Davare, Monika. / Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 3. pp. 676-685.
@article{99ca08f87be4478fb539de86dc6d94dd,
title = "Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma",
abstract = "Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4{\%}) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. Implications: A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.",
author = "Lara Davis and Nusser, {Kevin D.} and Joanna Przybyl and Janet Pittsenbarger and Hofmann, {Nicolle E.} and Sushama Varma and Sujay Vennam and Maria Debiec-Rychter and {van de Rijn}, Matt and Monika Davare",
year = "2019",
month = "3",
day = "1",
doi = "10.1158/1541-7786.MCR-18-1075",
language = "English (US)",
volume = "17",
pages = "676--685",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma

AU - Davis, Lara

AU - Nusser, Kevin D.

AU - Przybyl, Joanna

AU - Pittsenbarger, Janet

AU - Hofmann, Nicolle E.

AU - Varma, Sushama

AU - Vennam, Sujay

AU - Debiec-Rychter, Maria

AU - van de Rijn, Matt

AU - Davare, Monika

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. Implications: A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.

AB - Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. Implications: A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.

UR - http://www.scopus.com/inward/record.url?scp=85063083217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063083217&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-18-1075

DO - 10.1158/1541-7786.MCR-18-1075

M3 - Article

VL - 17

SP - 676

EP - 685

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 3

ER -