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

Abstract

Abstract
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
URI:	https://oak.novartis.com/id/eprint/26059