Identifying and targeting ROS1 gene fusions in non-small cell lung cancer

Kurtis D. Davies, Anh T. Le, Mariana F. Theodoro, Margaret C. Skokan, Dara L. Aisner, Eamon M. Berge, Luigi M. Terracciano, Federico Cappuzzo, Matteo Incarbone, Massimo Roncalli, Marco Alloisio, Armando Santoro, D. Ross Camidge, Marileila Varella-Garcia, Robert C. Doebele

Research output: Contribution to journalArticle

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Abstract

Purpose: Oncogenic gene fusions involving the 3′ region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. Experimental Design: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting. Results: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1fusion, whereas twoTMAsamples expressed theCD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival. Conclusions: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes. Clin Cancer Res; 18(17); 4570-9.

Original languageEnglish
Pages (from-to)4570-4579
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number17
DOIs
Publication statusPublished - Sep 1 2012

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Gene Fusion
Non-Small Cell Lung Carcinoma
Neoplasms
Phosphotransferases
Critical Pathways
Reverse Transcriptase Polymerase Chain Reaction
Cell Cycle
Flow Cytometry
Research Design
Therapeutics
Down-Regulation
Western Blotting
Cell Line
Polymerase Chain Reaction
Survival
Growth
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Davies, K. D., Le, A. T., Theodoro, M. F., Skokan, M. C., Aisner, D. L., Berge, E. M., ... Doebele, R. C. (2012). Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical Cancer Research, 18(17), 4570-4579. https://doi.org/10.1158/1078-0432.CCR-12-0550

Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. / Davies, Kurtis D.; Le, Anh T.; Theodoro, Mariana F.; Skokan, Margaret C.; Aisner, Dara L.; Berge, Eamon M.; Terracciano, Luigi M.; Cappuzzo, Federico; Incarbone, Matteo; Roncalli, Massimo; Alloisio, Marco; Santoro, Armando; Camidge, D. Ross; Varella-Garcia, Marileila; Doebele, Robert C.

In: Clinical Cancer Research, Vol. 18, No. 17, 01.09.2012, p. 4570-4579.

Research output: Contribution to journalArticle

Davies, KD, Le, AT, Theodoro, MF, Skokan, MC, Aisner, DL, Berge, EM, Terracciano, LM, Cappuzzo, F, Incarbone, M, Roncalli, M, Alloisio, M, Santoro, A, Camidge, DR, Varella-Garcia, M & Doebele, RC 2012, 'Identifying and targeting ROS1 gene fusions in non-small cell lung cancer', Clinical Cancer Research, vol. 18, no. 17, pp. 4570-4579. https://doi.org/10.1158/1078-0432.CCR-12-0550
Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical Cancer Research. 2012 Sep 1;18(17):4570-4579. https://doi.org/10.1158/1078-0432.CCR-12-0550
Davies, Kurtis D. ; Le, Anh T. ; Theodoro, Mariana F. ; Skokan, Margaret C. ; Aisner, Dara L. ; Berge, Eamon M. ; Terracciano, Luigi M. ; Cappuzzo, Federico ; Incarbone, Matteo ; Roncalli, Massimo ; Alloisio, Marco ; Santoro, Armando ; Camidge, D. Ross ; Varella-Garcia, Marileila ; Doebele, Robert C. / Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 17. pp. 4570-4579.
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AU - Aisner, Dara L.

AU - Berge, Eamon M.

AU - Terracciano, Luigi M.

AU - Cappuzzo, Federico

AU - Incarbone, Matteo

AU - Roncalli, Massimo

AU - Alloisio, Marco

AU - Santoro, Armando

AU - Camidge, D. Ross

AU - Varella-Garcia, Marileila

AU - Doebele, Robert C.

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N2 - Purpose: Oncogenic gene fusions involving the 3′ region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. Experimental Design: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting. Results: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1fusion, whereas twoTMAsamples expressed theCD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival. Conclusions: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes. Clin Cancer Res; 18(17); 4570-9.

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