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|Ref Type||Journal Article|
|Authors||Balko JM, Schwarz LJ, Luo N, Estrada MV, Giltnane JM, Dávila-González D, Wang K, Sánchez V, Dean PT, Combs SE, Hicks D, Pinto JA, Landis MD, Doimi FD, Yelensky R, Miller VA, Stephens PJ, Rimm DL, Gómez H, Chang JC, Sanders ME, Cook RS, Arteaga CL|
|Title||Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence.|
|Journal||Science translational medicine|
|Date||2016 Apr 13|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|JAK2 amp||triple-receptor negative breast cancer||sensitive||NVP-BSK805 + Paclitaxel||Preclinical - Pdx||Actionable||In a preclinical study, NVP-BSK805 with Abraxane (paclitaxel) inhibited tumor growth in triple-negative breast cancer patient-derived xenograft models with JAK2 amplification (PMID: 27075627).||27075627|
|JAK2 amp||triple-receptor negative breast cancer||sensitive||NVP-BSK805||Preclinical - Pdx||Actionable||In a preclinical study, NVP-BSK805 inhibited tumor growth in triple-negative breast cancer patient-derived xenograft models harboring JAK2 amplification (PMID: 27075627).||27075627|
|JAK2 over exp||triple-receptor negative breast cancer||sensitive||NVP-BSK805 + Paclitaxel||Preclinical - Pdx||Actionable||In a preclinical study, NVP-BSK805 with Abraxane (paclitaxel) inhibited tumor growth in patient-derived xenograft models of triple-negative breast cancer with JAK2 overexpression (PMID: 27075627).||27075627|