title: Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence.
abstract: 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.
authors.affiliation: 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.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Schwarz
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Mónica V
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: 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.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Giltnane
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dávila-González
authors.affiliation: Foundation Medicine, Cambridge, MA 02142, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Dean
authors.affiliation: Departments of Pathology and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Hicks
authors.affiliation: Oncosalud, Lima 41, Perú.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Pinto
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.affiliation: Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima 34, Perú.
authors.forename: Franco D
authors.initials: FD
authors.lastname: Doimi
authors.affiliation: Foundation Medicine, Cambridge, MA 02142, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine, Cambridge, MA 02142, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, MA 02142, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Departments of Pathology and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima 34, Perú.
authors.forename: Henry
authors.initials: H
authors.lastname: Gómez
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.affiliation: 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.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2