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Ref Type Journal Article
PMID (26455322)
Authors Arts FA, Chand D, Pecquet C, Velghe AI, Constantinescu S, Hallberg B, Demoulin JB
Title PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib.
Journal Vol Issue Date Pages Journal Short Title
Oncogene 35 25 2016 Jun 23 3239-48 Oncogene
URL
Abstract Text Recently, germline and somatic heterozygous mutations in the platelet-derived growth factor receptor β (PDGFRB) have been associated with familial infantile myofibromatosis (IM), which is characterized by soft tissue tumors, and overgrowth syndrome, a disease that predisposes to cancer. These mutations have not been functionally characterized. In the present study, the activity of three PDGFRB mutants associated with familial IM (R561C, P660T and N666K) and one PDGFRB mutant found in patients with overgrowth syndrome (P584R) was tested in various models. The P660T mutant showed no difference with the wild-type receptor, suggesting that it might represent a polymorphic variant unrelated to the disease. By contrast, the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents. In particular, the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. The distinct phenotypes associated with these two mutations could be related to this difference of potency. Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. In conclusion, the PDGFRB mutations previously identified in familial IM and overgrowth syndrome activate the receptor in the absence of ligand, supporting the hypothesis that these mutations cause the diseases. Moreover, imatinib seems to be a promising treatment for patients carrying these mutations. To our knowledge, these are the first confirmed gain-of-function point mutations of PDGFRB in human cancer.

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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
PDGFRB N666K missense gain of function PDGFRB N666K lies within the protein kinase domain of the Pdgfrb protein (PMID: 26455322). N666K results in increased Pdgfrb phosphorylation (PMID: 38741091), constitutive activation of Pdgfrb, and transformation in cell culture (PMID: 26455322).
PDGFRB P584R missense gain of function PDGFRB P584R lies within the cytoplasmic domain of the Pdgfrb protein (UniProt.org). P584R confers a gain of function to Pdgfrb, as indicated by activation of downstream signaling, increased proliferation, and transformation of cultured cells (PMID: 26455322).
PDGFRB P660T missense unknown PDGFRB P660T lies within the protein kinase domain of the Pdgfrb protein (UniProt.org). The functional effect of P660T is conflicting as it demonstrates activity similar to wild-type Pdgfrb and is not transforming in cultured cells in one study (PMID: 26455322) but results in constitutive phosphorylation of Pdgfrb and increased downstream signaling in cultured cells in another study (PMID: 33509954), and therefore, its effect on Pdgfrb protein function is unknown.
PDGFRB R561C missense gain of function PDGFRB R561C lies within the cytoplasmic domain of the Pdgfrb protein (UniProt.org). R561C results in constitutive phosphorylation of Pdgfrb, activation of downstream signaling (PMID: 33509954, PMID: 26455322), and is transforming in cell culture (PMID: 26455322).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRB P584R Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB P584R in culture (PMID: 26455322). 26455322
PDGFRB P584R Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB P584R in culture (PMID: 26455322). 26455322
PDGFRB N666K Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB N666K in culture (PMID: 26455322). 26455322
PDGFRB N666K Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB N666K in culture (PMID: 26455322). 26455322
PDGFRB R561C Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB R561C in culture (PMID: 26455322). 26455322
PDGFRB R561C Advanced Solid Tumor sensitive Nilotinib Preclinical - Cell culture Actionable In a preclinical study, Tasigna (nilotinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB R561C in culture (PMID: 26455322). 26455322
PDGFRB P584R Advanced Solid Tumor sensitive Nilotinib Preclinical - Cell culture Actionable In a preclinical study, Tasigna (nilotinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB P584R in culture (PMID: 26455322). 26455322
PDGFRB R561C Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB R561C in culture (PMID: 26455322). 26455322
PDGFRB N666K Advanced Solid Tumor sensitive Nilotinib Preclinical - Cell culture Actionable In a preclinical study,Tasigna (nilotinib) inhibited PDGFRB downstream signaling and proliferation of transformed cells expressing PDGFRB N666K in culture (PMID: 26455322). 26455322