Research ArticleCancer

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

Science Translational Medicine  13 Apr 2016:
Vol. 8, Issue 334, pp. 334ra53
DOI: 10.1126/scitranslmed.aad3001

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Playing with JAKs

Janus kinase (JAK) proteins are well known to be involved in cancer progression, and drugs such as ruxolitinib target these proteins, specifically JAK1 and JAK2. Balko et al. demonstrated frequent amplification of JAK2 in triple-negative breast cancer, a particularly aggressive and deadly form of the disease and showed that it was associated with decreased survival. The authors observed that JAK2 inhibition was effective in treating this type of breast cancer in mouse models. They also found that inhibiting JAK1 along with JAK2 in this context rendered the treatment ineffective, explaining why ruxolitinib does not work in triple-negative breast cancer and suggesting that specific JAK2 inhibitors may be a better approach.

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.

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