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Ref Type Journal Article
PMID (30389923)
Authors Ip CKM, Ng PKS, Jeong KJ, Shao SH, Ju Z, Leonard PG, Hua X, Vellano CP, Woessner R, Sahni N, Scott KL, Mills GB
Title Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies.
Journal Nature communications
Vol 9
Issue 1
Date 2018 11 02
URL
Abstract Text Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.

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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
PDGFRA D842V missense gain of function PDGFRA D842V lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D842V results in ligand-independent phosphorylation of Pdgfra, activation of downstream signaling, and is transforming in culture (PMID: 22745105, PMID: 23752188, PMID: 29533785, PMID: 30253204) and confers resistance to PDGFRA inhibitors (PMID: 30389923, PMID: 18955458). Y
PDGFRA E1068K missense no effect - predicted PDGFRA E1068K lies within the cytoplasmic domain of the Pdgfra protein (UniProt.org). E1068K has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA E699D missense no effect - predicted PDGFRA E699D lies within the protein kinase domain of the Pdgfra protein (UniProt.org). E699D has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA G185W missense no effect - predicted PDGFRA G185W lies within the Ig-like C2-type domain 2 of the Pdgfra protein (UniProt.org). G185W has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra (PMID: 29533785, PMID: 30389923).
PDGFRA G829E missense no effect - predicted PDGFRA G829E lies within the protein kinase domain of the Pdgfra protein (UniProt.org). G829E has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra (PMID: 29533785, PMID: 30389923).
PDGFRA P345S missense gain of function - predicted PDGFRA P345S lies within the Ig-like C2-type domain 4 of the Pdgfra protein (UniProt.org). P345S has not been biochemically characterized, but in one of two cell lines, P345S increased cell proliferation and cell viability compared to wild-type Pdgfra (PMID: 29533785, PMID: 30389923).
PDGFRA P414L missense no effect - predicted PDGFRA P414L lies within the Ig-like C2-type domain 5 of the Pdgfra protein (UniProt.org). P414L has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923)).
PDGFRA P577T missense gain of function - predicted PDGFRA P577T lies within the juxtamembrane domain of the Pdgfra protein (PMID: 24132921). P577T has not been biochemically characterized, but is predicted to confer a gain of function on the Pdgfra protein as demonstrated by increased transformation ability in one of two cell lines in culture (PMID: 29533785, PMID: 30389923).
PDGFRA R1037K missense no effect - predicted PDGFRA R1037K lies within the cytoplasmic domain of the Pdgfra protein (UniProt.org). R1037K has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA R340Q missense no effect - predicted PDGFRA R340Q lies within the Ig-like C2-type domain 4 of the Pdgfra protein (UniProt.org). R340Q has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra (PMID: 29533785, PMID: 30389923).
PDGFRA R764C missense no effect - predicted PDGFRA R764C lies within the protein kinase domain of the Pdgfra protein (UniProt.org). R764C has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA S308F missense no effect - predicted PDGFRA S308F does not lies within any known functional domains of the Pdgfra protein (UniProt.org). S308F has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA S478P missense no effect PDGFRA S478P lies within the extracellular domain and the Ig-like C2-type 5 domain of the Pdgfra protein (UniProt.org). S478P results in ligand-dependent phosphorylation (PMID: 12949711), and cell proliferation and viability levels similar to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923)
PDGFRA T153A missense no effect - predicted PDGFRA T153A lies within the Ig-like C2-type domain 2 of the Pdgfra protein (UniProt.org). T153A has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra (PMID: 29533785, PMID: 30389923).
PDGFRA V193I missense no effect - predicted PDGFRA V193I lies within the Ig-like C2-type domain 2 of the Pdgfra protein (UniProt.org). V193I has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA V484M missense no effect - predicted PDGFRA V484M lies within the Ig-like C2-type domain 5 of the Pdgfra protein (UniProt.org). V484M has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Pdgfra in culture (PMID: 29533785, PMID: 30389923).
PDGFRA Y288C missense gain of function - predicted PDGFRA Y288C lies within the Ig-like C2-type domain 3 of the Pdgfra protein (UniProt.org). Y288C results in constitutive activation of Pdgfra and downstream signaling, and increased transformation and migration compared to wild-type PDGFRA in cell culture (PMID: 29533785, PMID: 30389923), and is associated with PDGFRA inhibitor resistance (PMID: 30389923).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRA Y288C Advanced Solid Tumor sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment resulted in decreased proliferation of transformed cells expressing PDGFRA Y288C in culture (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor no benefit AZD9150 Preclinical - Cell culture Actionable In a preclinical study, ISIS-STAT3rx (AZD9150) did not decrease viability of transformed cells expressing PDGFRA Y288C in culture (PMID: 30389923). 30389923
PDGFRA V561D Advanced Solid Tumor sensitive Nilotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA V561D demonstrated sensitivity to Tasigna (nilotinib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA Y288C demonstrated resistance to Sutent (sunitinib) in culture (PMID: 30389923). 30389923
PDGFRA D842V Advanced Solid Tumor resistant Nilotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA D842V demonstrated resistance to Tasigna (nilotinib) in culture (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA Y288C demonstrated resistance to Crenolanib in culture (PMID: 30389923). 30389923
PDGFRA V561D Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA V561D demonstrated sensitivity to Gleevec (imatinib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA V561D Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA V561D demonstrated sensitivity to Sutent (sunitinib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA Y288C demonstrated resistance to Gleevec (imatinib) in culture (PMID: 30389923). 30389923
PDGFRA D842V Advanced Solid Tumor sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA D842V demonstrated sensitivity to Crenolanib in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA Y288C demonstrated sensitivity to GSK2126458 (omipalisib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA D842V Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA D842V demonstrated resistance to Gleevec (imatinib) in culture (PMID: 30389923). 30389923
PDGFRA D842V Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA D842V demonstrated resistance to Sutent (sunitinib) in culture (PMID: 30389923). 30389923
PDGFRA Y288C Advanced Solid Tumor resistant Nilotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA Y288C demonstrated resistance to Tasigna (nilotinib) in culture (PMID: 30389923). 30389923
PDGFRA V561D Advanced Solid Tumor sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA V561D demonstrated sensitivity to Crenolanib in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA D842V Advanced Solid Tumor sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA D842V demonstrated sensitivity to GSK2126458 (omipalisib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923
PDGFRA V561D Advanced Solid Tumor sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing PDGFRA V561D demonstrated sensitivity to GSK2126458 (omipalisib) in culture, resulting in decreased cell proliferation (PMID: 30389923). 30389923