Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence.

Autor:	Balko JM; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA. Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. carlos.arteaga@vanderbilt.edu justin.balko@vanderbilt.edu., Schwarz LJ; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA., Luo N; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA., Estrada MV; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA., Giltnane JM; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA., Dávila-González D; Houston Methodist Cancer Center, Houston, TX 77030, USA., Wang K; Foundation Medicine, Cambridge, MA 02142, USA., Sánchez V; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA., Dean PT; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA., Combs SE; Departments of Pathology and Medicine, Yale University, New Haven, CT 06520, USA., Hicks D; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA., Pinto JA; Oncosalud, Lima 41, Perú., Landis MD; Houston Methodist Cancer Center, Houston, TX 77030, USA., Doimi FD; Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima 34, Perú., Yelensky R; Foundation Medicine, Cambridge, MA 02142, USA., Miller VA; Foundation Medicine, Cambridge, MA 02142, USA., Stephens PJ; Foundation Medicine, Cambridge, MA 02142, USA., Rimm DL; Departments of Pathology and Medicine, Yale University, New Haven, CT 06520, USA., Gómez H; Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima 34, Perú., Chang JC; Houston Methodist Cancer Center, Houston, TX 77030, USA., Sanders ME; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA., Cook RS; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA., Arteaga CL; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA. Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. carlos.arteaga@vanderbilt.edu justin.balko@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2016 Apr 13; Vol. 8 (334), pp. 334ra53.
DOI:	10.1126/scitranslmed.aad3001
Abstrakt:	Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC without JAK2 amplification. Detection of JAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates of JAK2 amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available, JAK2 amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines with JAK2 copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore, JAK2 amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors. (Copyright © 2016, American Association for the Advancement of Science.)
Databáze:	MEDLINE
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