Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment

Neel, 2003, The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling, Trends Biochem Sci, 28, 284, 10.1016/S0968-0004(03)00091-4 Barford, 1998, Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2, Structure, 6, 249, 10.1016/S0969-2126(98)00027-6 LaRochelle, 2016, Structural and functional consequences of three cancer-associated mutations of the oncogenic phosphatase SHP2, Biochemistry, 55, 2269, 10.1021/acs.biochem.5b01287 LaRochelle, 2018, Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition, Nat Commun, 9, 4508, 10.1038/s41467-018-06823-9 Marasco, 2020, Molecular mechanism of SHP2 activation by PD-1 stimulation, Sci Adv, 6, 10.1126/sciadv.aay4458 Araki, 2003, Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors, J Biol Chem, 278, 41677, 10.1074/jbc.M306461200 Ruess, 2018, Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase, Nat Med, 24, 954, 10.1038/s41591-018-0024-8 Lu, 2001, Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling, Mol Cell, 8, 759, 10.1016/S1097-2765(01)00369-0 Sun, 2013, Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2, Nat Commun, 4, 2037, 10.1038/ncomms3037 Dance, 2008, The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway, Cell Signal, 20, 453, 10.1016/j.cellsig.2007.10.002 Schlessinger, 2000, Cell signaling by receptor tyrosine kinases, Cell, 103, 211, 10.1016/S0092-8674(00)00114-8 Simanshu, 2017, RAS proteins and their regulators in human disease, Cell, 170, 17, 10.1016/j.cell.2017.06.009 Pádua, 2018, Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2, Nat Commun, 9, 4507, 10.1038/s41467-018-06814-w Rehman, 2019, Gain-of-Function SHP2 E76Q mutant rescuing autoinhibition mechanism associated with juvenile myelomonocytic leukemia, J Chem Inf Model, 59, 3229, 10.1021/acs.jcim.9b00353 Zhang, 2020, Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2, J Biol Chem, 295, 6187, 10.1074/jbc.RA119.010274 Tartaglia, 2005, Germ-line and somatic PTPN11 mutations in human disease, Eur J Med Genet, 48, 81, 10.1016/j.ejmg.2005.03.001 Chan, 2008, The tyrosine phosphatase Shp2 (PTPN11) in cancer, Cancer Metastasis Rev, 27, 179, 10.1007/s10555-008-9126-y Bentires-Alj, 2004, Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia, Cancer Res, 64, 8816, 10.1158/0008-5472.CAN-04-1923 Martinelli, 2006, Activating PTPN11 mutations play a minor role in pediatric and adult solid tumors, Cancer Genet Cytogenet, 166, 124, 10.1016/j.cancergencyto.2005.10.003 Aoki, 2016, Recent advances in RASopathies, J Hum Genet, 61, 33, 10.1038/jhg.2015.114 Zhu, 2020, Phase separation of disease-associated SHP2 mutants underlies MAPK Hyperactivation, Cell, 183, 490, 10.1016/j.cell.2020.09.002 Mullard, 2018, Phosphatases start shedding their stigma of undruggability, Nat Rev Drug Discov, 17, 847, 10.1038/nrd.2018.201 Tsutsumi, 2018, Off-target inhibition by active site-targeting SHP2 inhibitors, FEBS Open Bio, 8, 1405, 10.1002/2211-5463.12493 Grosskopf, 2015, Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells invitro and invivo, ChemMedChem, 10, 815, 10.1002/cmdc.201500015 Schmidt, 2011, Dynamic substrate enhancement for the identification of specific, second-site-binding fragments targeting a set of protein tyrosine phosphatases, ChemBioChem, 12, 2640, 10.1002/cbic.201100414 Garcia Fortanet, 2016, Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor, J Med Chem, 59, 7773, 10.1021/acs.jmedchem.6b00680 Chen, 2016, Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases, Nature, 535, 148, 10.1038/nature18621 Ran, 2016, Sticking it to cancer with molecular glue for SHP2, Cancer Cell, 30, 194, 10.1016/j.ccell.2016.07.010 Nichols, 2018, RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers, Nat Cell Biol, 20, 1064, 10.1038/s41556-018-0169-1 Bagdanoff, 2019, Optimization of fused Bicyclic allosteric SHP2 inhibitors, J Med Chem, 62, 1781, 10.1021/acs.jmedchem.8b01725 Sarver, 2019, 6-Amino-3-methylpyrimidinones as potent, selective, and orally efficacious SHP2 inhibitors, J Med Chem, 62, 1793, 10.1021/acs.jmedchem.8b01726 Fodor, 2018, Dual allosteric inhibition of SHP2 phosphatase, ACS Chem Biol, 13, 647, 10.1021/acschembio.7b00980 Wylie, 2017, The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1, Nature, 543, 733, 10.1038/nature21702 Wang, 2020, Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein, J Med Chem, 63, 7510, 10.1021/acs.jmedchem.0c00471 Lin, 2017, Targeting ALK: precision medicine takes on drug resistance, Cancer Discov, 7, 137, 10.1158/2159-8290.CD-16-1123 Sun, 2018, Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099, Leukemia, 32, 1246, 10.1038/s41375-018-0020-5 Wildes, 2018, Abstract 4877: allosteric inhibition of SHP2 variants containing cancer-associated activating mutations, Cancer Res, 78, 4877, 10.1158/1538-7445.AM2018-4877 Moore, 2020, RAS-targeted therapies: is the undruggable drugged?, Nat Rev Drug Discov, 19, 533, 10.1038/s41573-020-0068-6 Haigis, 2017, KRAS alleles: the devil is in the detail, Trends Cancer, 3, 686, 10.1016/j.trecan.2017.08.006 Hunter, 2015, Biochemical and structural analysis of common cancer-associated KRAS mutations, Mol Cancer Res, 13, 1325, 10.1158/1541-7786.MCR-15-0203 Smith, 2013, NMR-based functional profiling of RASopathies and oncogenic RAS mutations, Proc Natl Acad Sci, 110, 4574, 10.1073/pnas.1218173110 Li, 2018, A model for RAS mutation patterns in cancers: finding the sweet spot, Nat Rev Cancer, 18, 767, 10.1038/s41568-018-0076-6 Lito, 2016, Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism, Science, 351, 604, 10.1126/science.aad6204 Xue, 2020, Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition, Nature, 577, 421, 10.1038/s41586-019-1884-x Mainardi, 2018, SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo, Nat Med, 24, 961, 10.1038/s41591-018-0023-9 Nissan, 2014, Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence, Cancer Res, 74, 2340, 10.1158/0008-5472.CAN-13-2625 Yao, 2017, Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS, Nature, 548, 234, 10.1038/nature23291 Bivona, 2016, A framework for understanding and targeting residual disease in oncogene-driven solid cancers, Nat Med, 22, 472, 10.1038/nm.4091 Rotow, 2017, Understanding and targeting resistance mechanisms in NSCLC, Nat Rev Cancer, 17, 637, 10.1038/nrc.2017.84 Prahallad, 2015, PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs, Cell Rep, 12, 1978, 10.1016/j.celrep.2015.08.037 Dardaei, 2018, SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors, Nat Med, 24, 512, 10.1038/nm.4497 Hao, 2020, Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling, Clin Cancer Res Jänne, 2017, Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non–small cell lung cancer: the SELECT-1 randomized clinical trial, J Am Med Assoc, 317, 1844, 10.1001/jama.2017.3438 Planchard, 2017, Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial, Lancet Oncol, 18, 1307, 10.1016/S1470-2045(17)30679-4 Caunt, 2015, MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road, Nat Rev Cancer, 15, 577, 10.1038/nrc4000 Fedele, 2018, SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models, Cancer Discov, 8, 1237, 10.1158/2159-8290.CD-18-0444 Lu, 2019, SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors, Mol Cancer Ther, 18, 1323, 10.1158/1535-7163.MCT-18-0852 Wong, 2018, Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition, Nat Med, 24, 968, 10.1038/s41591-018-0022-x Ahmed, 2019, SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors, Cell Rep, 26, 65, 10.1016/j.celrep.2018.12.013 Klempner, 2020, Can the help match the hype? KRASG12C-Specific inhibitors and beyond, Cancer Discov, 10, 20, 10.1158/2159-8290.CD-19-1255 Lou, 2019, KRASG12C inhibition produces a driver-limited state revealing collateral dependencies, Sci Signal, 12, eaaw9450, 10.1126/scisignal.aaw9450 Ryan, 2020, Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition, Clin Cancer Res, 26, 1633, 10.1158/1078-0432.CCR-19-3523 LaMarche, 2020, Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancer, J Med Chem, 10.1021/acs.jmedchem.0c01170 Zhao, 2019, SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade, Acta Pharm Sin B, 9, 304, 10.1016/j.apsb.2018.08.009 Ou, 2020, A12 the SHP2 inhibitor RMC-4630 in patients with KRAS-mutant non-small cell lung cancer: preliminary evaluation of a first-in-man phase 1 clinical trial, J Thorac Oncol, 15, S15, 10.1016/j.jtho.2019.12.041 Grossmann, 2010, Chapter 2 - the tyrosine phosphatase Shp2 in development and cancer, 53, 10.1016/S0065-230X(10)06002-1 Neel, 2010, Chapter 98 - SH2 domain-containing protein-tyrosine phosphatases, 771 Baltanás, 2013, Functional redundancy of Sos1 and Sos2 for lymphopoiesis and organismal homeostasis and survival, Mol Cell Biol, 33, 4562, 10.1128/MCB.01026-13 Chan, 2011, Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells, Blood, 117, 4253, 10.1182/blood-2010-11-319517 Mazharian, 2013, Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function, Blood, 121, 4205, 10.1182/blood-2012-08-449272 Rota, 2018, Shp-2 is dispensable for establishing T cell exhaustion and for PD-1 signaling in vivo, Cell Rep, 23, 39, 10.1016/j.celrep.2018.03.026 Binnewies, 2018, Understanding the tumor immune microenvironment (TIME) for effective therapy, Nat Med, 24, 541, 10.1038/s41591-018-0014-x Patel, 2018, Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies, Immunity, 48, 417, 10.1016/j.immuni.2018.03.007 Sharma, 2020, Dissecting the mechanisms of immune checkpoint therapy, Nat Rev Immunol, 20, 75, 10.1038/s41577-020-0275-8 Celis-Gutierrez, 2019, Quantitative interactomics in primary T cells provides a rationale for concomitant PD-1 and BTLA coinhibitor blockade in cancer immunotherapy, Cell Rep, 27, 3315, 10.1016/j.celrep.2019.05.041 Xu, 2020, PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2, J Cell Biol, 219 Hui, 2017, T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition, Science, 355, 1428, 10.1126/science.aaf1292 Lee, 1998, Molecular basis of T cell inactivation by CTLA-4, Science, 282, 2263, 10.1126/science.282.5397.2263 Wang, 2018, Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8 T cell dysfunction and maintain memory phenotype, Sci Immunol, 3, 10.1126/sciimmunol.aat7061 Quintana, 2020, Allosteric inhibition of SHP2 stimulates anti-tumor immunity by transforming the immunosuppressive environment, Cancer Res, 10.1158/0008-5472.CAN-19-3038 Fedele, 2020, SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling, J Exp Med, 218 Batth, 2018, Large-scale phosphoproteomics reveals Shp-2 phosphatase-dependent regulators of Pdgf receptor signaling, Cell Rep, 22, 2784, 10.1016/j.celrep.2018.02.038 Lu, 2020, Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR, Oncotarget, 11, 265, 10.18632/oncotarget.27435 Julien, 2011, Inside the human cancer tyrosine phosphatome, Nat Rev Cancer, 11, 35, 10.1038/nrc2980 Neel, 1997, Protein tyrosine phosphatases in signal transduction, Curr Opin Cell Biol, 9, 193, 10.1016/S0955-0674(97)80063-4 Pannifer, 1998, Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by X-ray Crystallography, J Biol Chem, 273, 10454, 10.1074/jbc.273.17.10454 Montagner, 2005, A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation, J Biol Chem, 280, 5350, 10.1074/jbc.M410012200 Agazie, 2003, Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling, Mol Cell Biol, 23, 7875, 10.1128/MCB.23.21.7875-7886.2003 Ren, 2004, Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor, J Biol Chem, 279, 8497, 10.1074/jbc.M312575200 Zhang, 2004, Shp2 regulates Src family kinase activity and Ras/Erk activation by controlling Csk recruitment, Mol Cell, 13, 341, 10.1016/S1097-2765(04)00050-4 Masoumi-Moghaddam, 2014, The developing story of Sprouty and cancer, Cancer Metastasis Rev, 33, 695, 10.1007/s10555-014-9497-1 Hanafusa, 2002, Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway, Nat Cell Biol, 4, 850, 10.1038/ncb867 Jarvis, 2006, Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases, Development, 133, 1133, 10.1242/dev.02255 Wakioka, 2001, Spred is a Sprouty-related suppressor of Ras signalling, Nature, 412, 647, 10.1038/35088082 Yan, 2020, Structural insights into the SPRED1-neurofibromin-KRAS complex and disruption of SPRED1-neurofibromin interaction by oncogenic EGFR, Cell Rep, 32, 107909, 10.1016/j.celrep.2020.107909 Quintanar-Audelo, 2011, Sprouty-related Ena/Vasodilator-stimulated Phosphoprotein Homology 1-Domain-containing protein (SPRED1), a tyrosine-protein phosphatase non-receptor type 11 (SHP2) substrate in the Ras/Extracellular signal-regulated kinase (ERK) pathway, J Biol Chem, 286, 23102, 10.1074/jbc.M110.212662 Eck, 1996, Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2, Nature, 379, 277, 10.1038/379277a0 Peled, 2018, Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor, Proc Natl Acad Sci, 115, E468, 10.1073/pnas.1710437115 Sheppard, 2004, PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ, FEBS Lett, 574, 37, 10.1016/j.febslet.2004.07.083 Sun, 2019