Reference Detail

Ref Type

Journal Article

PMID

(31182436)

Authors

Tarlock K, Alonzo TA, Wang YC, Gerbing RB, Ries R, Loken MR, Pardo L, Hylkema T, Joaquin J, Sarukkai L, Raimondi SC, Hirsch B, Sung L, Aplenc R, Bernstein I, Gamis AS, Meshinchi S, Pollard JA

Title

Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	16	2019 Aug 15	5038-5048	Clin Cancer Res

URL

Abstract Text

KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT-)] and mutation location (E8 vs. E17).KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT- (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT- patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.

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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
KIT	D419del	deletion	unknown	KIT D419del results in the deletion of an amino acid in Ig-like C2-type domain 5 of the Kit protein at amino acid 419 (UniProt.org). The functional effect of D419del is conflicting, as D419del has been reported to result in ligand-independent phosphorylation of Kit (PMID: 16143141, PMID: 15618474), and to result in lack of Kit phosphorylation and lack of cytokine-independent growth in cell culture (PMID: 31182436), and leads to Kit inactivation in response to Ptpre similar to wild-type Kit in cultured cells (PMID: 33732906).
KIT	D419G	missense	no effect - predicted	KIT D419G lies within Ig-like C2-type domain 5 of the Kit protein (UniProt.org). D419G does not result in Kit phosphorylation and is not transforming in cultured cells (PMID: 31182436), and therefore, is predicted to have no effect on Kit protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT D419G	hematologic cancer	no benefit	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing KIT D419G did not respond to treatment with Sprycel (dasatinib) in culture (PMID: 31182436).	31182436
KIT N822K	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N822K were sensitive to treatment with Crenolanib in culture, demonstrating reduced cell survival (PMID: 31182436).	31182436
KIT D419del	hematologic cancer	no benefit	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing KIT D419del did not respond to treatment with Sprycel (dasatinib) in culture (PMID: 31182436).	31182436
KIT D816V	hematologic cancer	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT D816V were sensitive to treatment with Sprycel (dasatinib) in culture, demonstrating reduced cell survival (PMID: 31182436).	31182436
KIT D419del	hematologic cancer	no benefit	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing KIT D419del did not respond to treatment with Crenolanib in culture (PMID: 31182436).	31182436
KIT D419G	hematologic cancer	no benefit	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing KIT D419G did not respond to treatment with Crenolanib in culture (PMID: 31182436).	31182436
KIT N822K	hematologic cancer	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N822K were sensitive to treatment with Sprycel (dasatinib) in culture, demonstrating reduced cell survival (PMID: 31182436).	31182436