Authors

Fredika M Robertson, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Emanuel F Petricoin Iii, The Center for Applied Proteomics and Molecular Medicine, George Mason University
Steven J Van Laere, Department of Oncology, KU Leuven
Francois Bertucci, Department of Molecular Oncology, Institut Paoli-Calmettes Marseille
Khoi Chu, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Sandra V Fernandez, Department of Medical Oncology, Thomas Jefferson UniversityFollow
Zhaomei Mu, Department of Medical Oncology, Thomas Jefferson UniversityFollow
Katherine Alpaugh, Protocol Support Laboratory, Fox Chase Cancer Center
Jianming Pei, Cancer Biology Laboratory, Fox Chase Cancer Center
Rita Circo, Istituto Regina Elena
Julia Wulfkuhle, The Center for Applied Proteomics and Molecular Medicine, George Mason University
Zaiming Ye, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Kimberly M Boley, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Hui Liu, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Ricardo Moraes, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Xuejun Zhang, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center
Ruggero Demaria, Istituto Regina Elena
Sanford H Barsky, Department of Pathology, The University of Nevada School of Medicine
Guoxian Sun, Genzyme Genetics
Massimo Cristofanilli, Department of Medical Oncology, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-1-2013

Comments

This article has been peer reviewed. It was published in: SpringerPlus.
Volume 2, Issue 1, 2013, Pages 1-12. The published version is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791224/. DOI: 10.1186/2193-1801-2-497.

Copyright © 2013 Robertson et al.

Abstract

Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK(+) IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics.

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