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Ref Type Journal Article
PMID (29568093)
Authors Sun X, Ren Y, Gunawan S, Teng P, Chen Z, Lawrence HR, Cai J, Lawrence NJ, Wu J
Title Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099.
Journal Leukemia
Vol 32
Issue 5
Date 2018 05
URL
Abstract Text

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PTPN11 A72V missense gain of function PTPN11 A72V lies within the SH2 domain 1 of the Ptpn11 protein (UniProt.org). A72V results in increased substrate dephosphorylation in an in vitro assay (PMID: 16358218), promotes growth factor-independent proliferation, and is associated with resistance to a Shp2 inhibitor in culture (PMID: 29568093). Y
PTPN11 D61Y missense gain of function PTPN11 D61Y lies within the SH2 domain 1 of the Ptpn11 protein (UniProt.org). D61Y results in increased activity of protein tyrosine phosphatase (PMID: 15834506), promotes proliferation in culture, and is associated with resistance to a Shp2 inhibitor (PMID: 12717436, PMID: 29568093). Y
PTPN11 E69K missense unknown PTPN11 E69K lies within the SH2 domain 1 of the Ptpn11 protein (UniProt.org). E69K results in similar cell proliferation and viability levels to wild-type Ptpn11 in once study (PMID: 29533785), but results in increased Ptpn11 phosphatase activity in an in vitro assay (PMID: 15604238) and growth factor-independent proliferation (PMID: 29568093) in other studies, and therefore, its effect on Ptpn11 protein function is unknown.
PTPN11 E76K missense gain of function PTPN11 E76K lies within the SH2 domain 1 of the Ptpn11 protein (UniProt.org). E76K confers a gain of function to the Ptpn11 protein as demonstrated by increased protein tyrosine phosphatase activity, Erk1/2 phosphorylation, and migration, invasion, and transformation of cultured cells (PMID: 17942397, PMID: 29568093, PMID: 31807022), and induces increased chromosome instability (PMID: 26755576), promotes tumor formation in mouse models (PMID: 31807022), and is associated with resistance to a Shp2 inhibitor (PMID: 29568093). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTPN11 D61Y myeloid leukemia resistant SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 had no effect on Erk1/2 phosphorylation, Bcl-xl expression, Parp cleavage, and growth of myeloid cells expressing PTPN11 D61Y in culture (PMID: 29568093). 29568093
PTPN11 A72V myeloid leukemia resistant SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 had no effect on Erk1/2 phosphorylation, Bcl-xl expression, Parp cleavage, and growth of myeloid cells expressing PTPN11 A72V in culture (PMID: 29568093). 29568093
PTPN11 E69K myeloid leukemia sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 inhibited Erk1/2 phosphorylation, Bcl-xl expression, Parp cleavage, and growth of myeloid cells expressing PTPN11 A72V in culture (PMID: 29568093). 29568093
PTPN11 dec exp myeloid leukemia resistant SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 had no effect on Erk1/2 phosphorylation, Bcl-xl expression, Parp cleavage, and growth of PTPN11 knock-out myeloid cells in culture (PMID: 29568093). 29568093
PTPN11 E76K myeloid leukemia resistant SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 had no effect on Erk1/2 phosphorylation, Bcl-xl expression, Parp cleavage, and growth of myeloid cells expressing PTPN11 E76K in culture (PMID: 29568093). 29568093