Kivonat:
The majority of patients develop resistance against
suppression of HER2-signaling mediated by trastuzumab in HER2
positive breast cancer (BC). HER2 overexpression activates
multiple signaling pathways, including the mitogen-activated
protein kinase (MAPK) cascade. MAPK phosphatases (MKPs) are
essential regulators of MAPKs and participate in many facets
of cellular regulation, including proliferation and apoptosis.
We aimed to identify whether differential MKPs are associated
with resistance to targeted therapy in patients previously
treated with trastuzumab. Using gene chip data of 88 HER2-
positive, trastuzumab treated BC patients, candidate MKPs were
identified by Receiver Operator Characteristics analysis
performed in R. Genes were ranked using their achieved area
under the curve (AUC) values and were further restricted to
markers significantly associated with worse survival.
Functional significance of the two strongest predictive
markers was evaluated in vitro by gene silencing in HER2
overexpressing, trastuzumab resistant BC cell lines SKTR and
JIMT-1. The strongest predictive MKPs were DUSP4/MKP-2
(AUC=0.75, p=0.0096) and DUSP6/MKP-3 (AUC=0.77, p=5.29E-05).
Higher expression for these correlated to worse survival
(DUSP4: HR=2.05, p=0.009 and DUSP6: HR=2, p=0.0015). Silencing
of DUSP4 had significant sensitization effects – viability of
DUSP4 siRNA transfected, trastuzumab treated cells decreased
significantly compared to scramble-siRNA transfected controls
(SKTR: p=0.016; JIMT-1: p=0.016). In contrast, simultaneous
treatment with DUSP6 siRNA and trastuzumab did not alter cell
proliferation. Our findings suggest that DUSP4 may represent a
new potential target to overcome trastuzumab resistance.
