SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer.
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Transformation, Neoplastic
Drug Resistance, Neoplasm
Extracellular Matrix
/ drug effects
Humans
Mice
Molecular Targeted Therapy
Neoplasm Metastasis
Phosphorylation
/ drug effects
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ metabolism
Signal Transduction
/ drug effects
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
14
02
2020
accepted:
24
09
2020
revised:
17
09
2020
pubmed:
10
10
2020
medline:
20
2
2021
entrez:
9
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33033382
doi: 10.1038/s41388-020-01488-5
pii: 10.1038/s41388-020-01488-5
pmc: PMC7714690
mid: NIHMS1632311
doi:
Substances chimiques
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7166-7180Subventions
Organisme : NIAAA NIH HHS
ID : R21 AA026675
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA232589
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA198929
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207751
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207288
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023168
Pays : United States
Références
Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Prev Biomark. 2017;26:809–15.
Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630–9.
pubmed: 16452222
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.
pubmed: 17192538
Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28:1301–7.
pubmed: 20142587
Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688–1700.
pubmed: 29146401
Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, et al. An acquired HER2 T798I gatekeeper mutation induces resistance to Neratinib in a patient with HER2 mutant–driven breast cancer. Cancer Discov. 2017;7:575–85.
pubmed: 28274957
pmcid: 5457707
Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13:4909–19.
pubmed: 17699871
Stuhlmiller TJ, Miller SM, Zawistowski JS, Nakamura K, Beltran AS, Duncan JS, et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains. Cell Rep. 2015;11:390–404.
pubmed: 25865888
pmcid: 4408261
Shattuck DL, Miller JK, Carraway KL, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 2008;68:1471–7.
pubmed: 18316611
Brown WS, Akhand SS, Wendt MK. FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition. Oncotarget. 2016;7:83424.
pubmed: 27825137
pmcid: 5347779
Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259–67.
pubmed: 26373574
Brown WS, Tan L, Smith A, Gray NS, Wendt MK. Covalent targeting of fibroblast growth factor receptor inhibits metastatic breast cancer. Mol Cancer Ther. 2016;15:2096–106.
pubmed: 27371729
pmcid: 5010989
Minuti G, Cappuzzo F, Duchnowska R, Jassem J, Fabi A, O’Brien T, et al. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br J Cancer. 2012;107:793.
pubmed: 22850551
pmcid: 3425981
Alexander PB, Chen R, Gong C, Yuan L, Jasper JS, Ding Y, et al. Distinct receptor tyrosine kinase subsets mediate anti-HER2 drug resistance in breast cancer. J Biol Chem. 2017;292:748–59.
pubmed: 27903634
Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Investig. 2006;116:1561–70.
pubmed: 16741576
Li D-M, Feng Y-M. Signaling mechanism of cell adhesion molecules in breast cancer metastasis: potential therapeutic targets. Breast Cancer Res Treat. 2011;128:7.
pubmed: 21499686
Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116.
pubmed: 20094046
Agazie YM, Hayman MJ. Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Mol Cell Biol. 2003;23:7875–86.
pubmed: 14560030
pmcid: 207628
Bunda S, Burrell K, Heir P, Zeng L, Alamsahebpour A, Kano Y, et al. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nat Commun. 2015;6:8859.
pubmed: 26617336
pmcid: 4674766
Liu W, Yu W-M, Zhang J, Chan RJ, Loh ML, Zhang Z, et al. Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia. 2017;31:1415.
pubmed: 27840422
Ran H, Tsutsumi R, Araki T, Neel BG. Sticking it to cancer with molecular glue for SHP2. Cancer Cell. 2016;30:194–6.
pubmed: 27505669
pmcid: 5558882
Araki T, Nawa H, Neel BG. Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors. J Biol Chem. 2003;278:41677–84.
pubmed: 12923167
Sun J, Lu S, Ouyang M, Lin L-J, Zhuo Y, Liu B, et al. Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2. Nat Commun. 2013;4:2037.
pubmed: 23792876
pmcid: 3777412
Dance M, Montagner A, Salles J-P, Yart A, Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal. 2008;20:453–9.
pubmed: 17993263
Zhang SQ, Tsiaras WG, Araki T, Wen G, Minichiello L, Klein R, et al. Receptor-specific regulation of phosphatidylinositol 3′-kinase activation by the protein tyrosine phosphatase Shp2. Mol Cell Biol. 2002;22:4062–72.
pubmed: 12024020
pmcid: 133866
Chen Y-NP, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535:148.
pubmed: 27362227
Zeng L-F, Zhang R-Y, Yu Z-H, Li S, Wu L, Gunawan AM, et al. Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem. 2014;57:6594–609.
pubmed: 25003231
pmcid: 4136714
Zhang R-Y, Yu Z-H, Zeng L, Zhang S, Bai Y, Miao J, et al. SHP2 phosphatase as a novel therapeutic target for melanoma treatment. Oncotarget. 2016;7:73817.
pubmed: 27650545
pmcid: 5342016
Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov. 2018;8:1237–49.
pubmed: 30045908
pmcid: 6170706
Zhao H, Martin E, Matalkah F, Shah N, Ivanov A, Ruppert JM, et al. Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis. Oncogene. 2019;38:2275–90.
pubmed: 30467378
Lan L, Holland JD, Qi J, Grosskopf S, Vogel R, Györffy B, et al. Shp2 signaling suppresses senescence in PyMT‐induced mammary gland cancer in mice. EMBO J. 2015;34:1493–508.
pubmed: 25736378
pmcid: 4474526
Aceto N, Sausgruber N, Brinkhaus H, Gaidatzis D, Martiny-Baron G, Mazzarol G, et al. Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat Med. 2012;18:529.
pubmed: 22388088
Ahmed TA, Adamopoulos C, Karoulia Z, Wu X, Sachidanandam R, Aaronson SA, et al. SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors. Cell Rep. 2019;26:65–78. e65
pubmed: 30605687
pmcid: 6396678
Zhou B, Gibson-Corley KN, Herndon ME, Sun Y, Gustafson-Wagner E, Teoh-Fitzgerald M, et al. Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma. Mol Cancer Res. 2014;12:143–54.
pubmed: 24002891
Wendt MK, Taylor MA, Schiemann BJ, Sossey-Alaoui K, Schiemann WP. Fibroblast growth factor receptor splice variants are stable markers of oncogenic transforming growth factor β1 signaling in metastatic breast cancers. Breast Cancer Res. 2014;16:R24.
pubmed: 24618085
pmcid: 4053226
Shibue T, Weinberg RA. Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci. 2009;106:10290–5.
pubmed: 19502425
Pulaski BA, Ostrand‐Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol. 2000;39:20.22. 21–20.22. 16.
Shinde A, Libring S, Alpsoy A, Abdullah A, Schaber JA, Solorio L, et al. Autocrine fibronectin inhibits breast cancer metastasis. Mol Cancer Res. 2018;16:1579–89.
pubmed: 29934326
pmcid: 6511995
Ali R, Brown W, Purdy SC, Davisson VJ, Wendt MK. Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand. Cell Death Dis. 2018;9:1–12.
Montagner A, Yart A, Dance M, Perret B, Salles J-P, Raynal P. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J Biol Chem. 2005;280:5350–60.
pubmed: 15574420
Koyama T, Nakaoka Y, Fujio Y, Hirota H, Nishida K, Sugiyama S, et al. Interaction of scaffolding adaptor protein Gab1 with tyrosine phosphatase SHP2 negatively regulates IGF-I-dependent myogenic differentiation via the ERK1/2 signaling pathway. J Biol Chem. 2008;283:24234–44.
pubmed: 18577518
pmcid: 3259763
Hadari Y, Kouhara H, Lax I, Schlessinger J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol. 1998;18:3966–73.
pubmed: 9632781
pmcid: 108981
Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y, et al. Tyrosine phosphorylation sites on FRS2α responsible for Shp2 recruitment are critical for induction of lens and retina. Proc Natl Acad Sci. 2004;101:17144–9.
pubmed: 15569927
Cunnick JM, Dorsey JF, Munoz-Antonia T, Mei L, Wu J. Requirement of SHP2 binding to Grb2-associated binder-1 for mitogen-activated protein kinase activation in response to lysophosphatidic acid and epidermal growth factor. J Biol Chem. 2000;275:13842–8.
pubmed: 10788507
Wendt MK, Taylor MA, Schiemann BJ, Schiemann WP. Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer. Mol Biol Cell. 2011;22:2423–35.
pubmed: 21613543
pmcid: 3135469
Barkan D, El Touny LH, Michalowski AM, Smith JA, Chu I, Davis AS, et al. Metastatic growth from dormant cells induced by a col-I–enriched fibrotic environment. Cancer Res. 2010;70:5706–16.
pubmed: 20570886
pmcid: 3436125
Zhao M, Guo W, Wu Y, Yang C, Zhong L, Deng G, et al. SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade. Acta Pharm Sin B. 2019;9:304–15.
pubmed: 30972278
Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–17.
pubmed: 22641383
pmcid: 3371732
Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res. 2019;7:1457–71.
pubmed: 31331945
Ye T, Wei X, Yin T, Xia Y, Li D, Shao B, et al. Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis. Breast Cancer Res Treat. 2014;143:435–46.
pubmed: 24398778
Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res. 2009;11:R68.
pubmed: 19740433
pmcid: 2790843
Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.
pubmed: 20068163
Wei T, Simko V, Levy M, Xie Y, Jin Y, Zemla J. Package ‘corrplot’. Statistician. 2017;56:e24.