Journal article
Hao Chen, Sarah Libring, K. Ruddraraju, Jinmin Miao, Luis Solorio, Zhon-Yin Zhang, Michael K. Wendt
Oncogene, 2020
Oncogene, 2020
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APA
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Chen, H., Libring, S., Ruddraraju, K., Miao, J., Solorio, L., Zhang, Z.-Y., & Wendt, M. K. (2020). SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer. Oncogene.
Chicago/Turabian
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Chen, Hao, Sarah Libring, K. Ruddraraju, Jinmin Miao, Luis Solorio, Zhon-Yin Zhang, and Michael K. Wendt. “SHP2 Is a Multifunctional Therapeutic Target in Drug Resistant Metastatic Breast Cancer.” Oncogene (2020).
MLA
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Chen, Hao, et al. “SHP2 Is a Multifunctional Therapeutic Target in Drug Resistant Metastatic Breast Cancer.” Oncogene, 2020.
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@article{hao2020a,
title = {SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer},
year = {2020},
journal = {Oncogene},
author = {Chen, Hao and Libring, Sarah and Ruddraraju, K. and Miao, Jinmin and Solorio, Luis and Zhang, Zhon-Yin and Wendt, Michael K.}
}
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.