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Tumors with amplifications of JAK2 at the 9p24 loci in TNBC demonstrate JAK2-specific dependency

Balko, Justin M and Arteaga, Carlos L (2016) Tumors with amplifications of JAK2 at the 9p24 loci in TNBC demonstrate JAK2-specific dependency. Sci Transl Med., 8 (334). pp. 334-353. ISSN 1946-6242


Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the
culprit genes that apply oncogenic functionality within this locus remain unclear. In performing
targeted next-generation sequencing across a series of residual disease specimens from triple negative breast cancer patients that had been treated with neoadjuvant chemotherapy, we
identified a series of 9p24-amplified patients, several of which contained focal amplifications that
included the Janus kinase-2 gene. These patients had markedly inferior recurrence-free and
overall survival rates after definitive surgery. Presence of JAK2/9p24 amplifications occurred at
higher rates in chemotherapy-treated TNBC patients than in other primary untreated TNBC or
basal-like breast cancers, or in other subtypes. Similar rates of JAK2 amplification were
confirmed in patient-derived xenograft models. In several cases where longitudinal specimens
were available, JAK2 amplification appeared to be selected for during neoadjuvant
chemotherapy and eventual metastatic spread, suggesting a role in tumorgenicity and
chemoresistance, phenotypes often attributed to a putative cancer stem cell-like population. In
cell line models of JAK2 gain or amplification, we noted that specific inhibition of JAK2-STAT6
signaling reduced mammosphere potential and cooperated with chemotherapy in in vivo models
to reduce tumor growth, while inhibition of JAK1-STAT3 signaling had little effect or
counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific
inhibitors may be more efficacious than dual JAK1/2 inhibitors clinically in the management of
TNBCs with JAK2 amplification. Furthermore, we identify a potential biomarker for JAK2-
dependency that may mark those patients who could benefit from the addition of JAK2 inhibitors
to chemotherapy in clinical trials.

Item Type: Article
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45


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