Abstract
Metastatic breast cancer (MBC) is an extremely recalcitrant disease capable of bypassing current targeted therapies via engagement of several growth promoting pathways. SH2 containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase known to facilitate growth and survival signaling downstream of numerous receptor inputs. Herein, we used inducible genetic depletion and two distinct pharmacological inhibitors to investigate the therapeutic potential of targeting SHP2 in MBC. Cells that acquired resistance to the ErbB kinase inhibitor, neratinib, displayed increased phosphorylation of SHP2 at the Y542 activation site. In addition, higher levels of SHP2 phosphorylation, but not expression, were associated with decreased survival of breast cancer patients. Pharmacological inhibition of SHP2 activity blocked ERK1/2 and AKT signaling generated from exogenous stimulation with FGF2, PDGF, and hGF and readily prevented MBC cell growth induced by these factors. SHP2 was also phosphorylated upon engagement of the extracellular matrix (ECM) via focal adhesion kinase. Consistent with the potential of SHP2-targeted compounds as therapeutic agents, the growth inhibitory property of SHP2 blockade was enhanced in ECM-rich 3D culture environments. In vivo blockade of SHP2 in the adjuvant setting decreased pulmonary metastasis and extended the survival of systemic tumor-bearing mice. Finally, inhibition of SHP2 in combination with FGFR-targeted kinase inhibitors synergistically blocked the growth of MBC cells. Overall, our findings support the conclusion that SHP2 constitutes a shared signaling node allowing MBC cells to simultaneously engage a diversity of growth and survival pathways, including those derived from the ECM.
Highlights
Stage IV, metastatic breast cancer (MBC) is a major clinical challenge, with 5 year survival rates currently at ~23% [1]
Drug-resistant progression of MBC can occur due to signaling events generated from multiple receptor tyrosine kinases (RTKs) and can be further influenced by interactions with the extracellular matrix (ECM)
Recent findings have begun to illustrate the oncogenic roles of Src homology region 2 (SH2) containing protein tyrosine phosphatase-2 (SHP2) in breast cancer, mechanistic understanding of SHP2 signaling and the therapeutic value of targeting SHP2 in drug resistant MBC was still limited [30,31,32]
Summary
Stage IV, metastatic breast cancer (MBC) is a major clinical challenge, with 5 year survival rates currently at ~23% [1]. Identification and pharmacological inhibition of the shared targets of drug resistance and metastasis remains a major barrier to the development of effective therapeutics for the treatment of late-stage disease. Multiple experimental studies, including findings from our lab, describe a role for fibroblast growth factor receptor 1 (FGFR1) in acquired and inherent resistance to HER2targeted therapeutics [7,8,9,10]. The locus encoding FGFR1 is amplified in 14% of breast cancer patients, and FGFR1 expression can be further upregulated through the process of epithelial–mesenchymal transition, a key driver of both drug resistance and metastasis [11, 12]. In addition to FGFR, multiple other receptor tyrosine kinases (RTKs) have been linked to both drug resistance and metastasis, including PDGFR, VEGFR, EGFR, and cMET [13,14,15]. We sought to identify signaling nodes shared between multiple RTKs and ECM signaling events as targeting these nodes may hold the key to the development of MBC therapies
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