Journal article
SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer
Oncogene, Vol.39(49), pp.7166-7180
12/03/2020
DOI: 10.1038/s41388-020-01488-5
PMCID: 7714690
PMID: 33033382
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.
Details
- Title: Subtitle
- SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer
- Creators
- Hao Chen - Purdue University West LafayetteSarah Libring - Purdue University West LafayetteKasi Viswanatharaju Ruddraraju - Purdue University West LafayetteJinmin Miao - Purdue University West LafayetteLuis Solorio - Purdue University West LafayetteZhong-Yin Zhang - Purdue University West LafayetteMichael K. Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.39(49), pp.7166-7180
- DOI
- 10.1038/s41388-020-01488-5
- PMID
- 33033382
- PMCID
- 7714690
- NLM abbreviation
- Oncogene
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Publisher
- Springer Nature
- Number of pages
- 15
- Grant note
- R01CA207751; RO1CA207288 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) RSG-CSM-130259 / American Cancer Society Research Scholar Grant; American Cancer Society Metavivor Foundation Translation Research Award P30CA023168 / SIRG Graduate Research Assistantships Award Purdue University Center for Cancer Research
- Language
- English
- Date published
- 12/03/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459628602771
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