Reference Detail

Ref Type Journal Article
PMID (27075627)
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
Vol 8
Issue 334
Date 2016 Apr 13
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
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