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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 Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 16
Date 2019 Aug 15
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 D419G missense no effect - predicted KIT D419G lies within the 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 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 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
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 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 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 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 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