Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical and experimental medicine	19	2	2019 May	201-210	Clin Exp Med

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
PLX9486	PLX9486	9	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PLX9486		PLX-9486\|PLX 9486\|Bezuclastinib\|CGT-9486\|CGT9486\|CGT 9486	KIT Inhibitor 57	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	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 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 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 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
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	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