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Ref Type Journal Article
PMID (30523507)
Authors Gebreyohannes YK, Burton EA, Wozniak A, Matusow B, Habets G, Wellens J, Cornillie J, Lin J, Nespi M, Wu G, Zhang C, Bollag G, Debiec-Rychter M, Sciot R, Schöffski P
Title PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors.
Journal Clinical and experimental medicine
Vol 19
Issue 2
Date 2019 May
URL
Abstract Text The purpose of the present study was to investigate the in vitro and in vivo activity of PLX9486, a tyrosine kinase inhibitor (TKI) targeting both primary KIT exon 9 and 11 and secondary exon 17 and 18 mutations in gastrointestinal stromal tumors (GISTs). Imatinib, a potent inhibitor of mutated KIT, has revolutionized the clinical management of advanced, metastatic GIST. However, secondary resistance develops mainly through acquired mutations in KIT exons 13/14 or exons 17/18. Second-line sunitinib potently inhibits KIT exon 13/14 mutants but is ineffective against exon 17 mutations. In our study, PLX9486 demonstrated in vitro nanomolar potency in inhibiting the growth and KIT phosphorylation of engineered BaF3 cells transformed with KIT exon 17 mutations (p.D816V) and with the double KIT exon 11/17 mutations (p.V560G/D816V). The in vivo efficacy of PLX9486 was evaluated using two imatinib-resistant GIST patient-derived xenograft (PDX) models. In UZLX-GIST9 (KIT: p.P577del;W557LfsX5;D820G), PLX9486 100 mg/kg/day resulted in significant inhibition of proliferation. Pharmacodynamic analysis showed a pronounced reduction in mitogen-activated protein kinase (MAPK) activation and other downstream effects of the KIT signaling pathway but no significant effect on KIT Y703 and Y719 phosphorylation. Similarly, in MRL-GIST1 (KIT: p.W557_K558del;Y823D) PLX9486 treatment led to significant tumor regression and strong inhibition of MAPK activation. Interestingly, the inhibitory effect on MAPK activation was evident even after a single dose of PLX9486. In conclusion, PLX9486 showed anti-tumor efficacy in patient-derived imatinib-resistant GIST xenograft models, mainly through inhibition of KIT signaling. These preclinical efficacy data encourage further testing of PLX9486 in the clinical setting.

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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
PLX9486 PLX-9486|PLX 9486|Bezuclastinib|CGT-9486|CGT9486|CGT 9486 KIT Inhibitor 53 PLX9486 is a Kit inhibitor with selective activity against primary (exon 9 and 11) and secondary (exon 17 and 18) Kit mutations, which may lead to growth inhibition in tumor cells expressing mutant c-Kit (Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 11509-11509, PMID: 30523507).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560G KIT D816V Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560G and D816V demonstrated resistance to Gleevec (imatinib) treatment in culture (PMID: 30523507). 30523507
KIT D816V Advanced Solid Tumor sensitive PLX9486 Preclinical - Cell culture Actionable In a preclinical study, PLX9486 treatment inhibited proliferation of Gleevec (imatinib)-resistant transformed cells expressing KIT D816V in culture (PMID: 30523507). 30523507
KIT V560G KIT D816V Advanced Solid Tumor sensitive PLX9486 Preclinical - Cell culture Actionable In a preclinical study, PLX9486 treatment inhibited proliferation of Gleevec (imatinib)-resistant transformed cells expressing KIT V560G and D816V in culture (PMID: 30523507). 30523507
KIT W557Lfs*5 KIT P577del KIT D820G gastrointestinal stromal tumor sensitive PLX9486 Preclinical - Pdx Actionable In a preclinical study, PLX9486 treatment decreased Mapk phosphorylation and Kit downstream signaling, inhibited proliferation, and reduced tumor growth in a Gleevec (imatinib)-resistant patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT P577del, W557Lfs*5, and D820G (PMID: 30523507). 30523507
KIT D816V Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) treatment did not inhibit proliferation of transformed cells expressing KIT D816V in culture (PMID: 30523507). 30523507
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive PLX9486 Preclinical - Pdx Actionable In a preclinical study, PLX9486 treatment decreased Mapk phosphorylation, inhibited proliferation, and reduced tumor growth and induced regression in a Gleevec (imatinib)-resistant patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and Y823D (PMID: 30523507). 30523507
KIT wild-type Advanced Solid Tumor sensitive PLX9486 Preclinical - Cell culture Actionable In a preclinical study, PLX9486 treatment inhibited proliferation of ligand-stimulated cells expressing wild-type KIT in culture (PMID: 30523507). 30523507