Reference Detail

Ref Type

Journal Article

PMID

(30544932)

Authors

Uras IZ, Maurer B, Nebenfuehr S, Zojer M, Valent P, Sexl V

Title

Therapeutic Vulnerabilities in FLT3-Mutant AML Unmasked by Palbociclib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of molecular sciences	19	12	2018 Dec 11		Int J Mol Sci

URL

Abstract Text

While significant progress has been made in the treatment of acute myeloid leukemia (AML), not all patients can be cured. Mutated in about 1/3 of de novo AML, the FLT3 receptor tyrosine kinase is an attractive target for drug development, activating mutations of the FLT3 map to the juxtamembrane domain (internal tandem duplications, ITD) or the tyrosine kinase domain (TKD), most frequently at codon D835. While small molecule tyrosine kinase inhibitors (TKI) effectively target ITD mutant forms, those on the TKD are not responsive. Moreover, FLT3 inhibition fails to induce a persistent response in patients due to mutational resistance. More potent compounds with broader inhibitory effects on multiple FLT3 mutations are highly desirable. We describe a critical role of CDK6 in the survival of FLT3⁺ AML cells as palbociclib induced apoptosis not only in FLT3⁻ITD⁺ cells but also in FLT3⁻D835Y⁺ cells. Antineoplastic effects were also seen in primary patient-derived cells and in a xenograft model, where therapy effectively suppressed tumor formation in vivo at clinically relevant concentrations. In cells with FLT3⁻ITD or -TKD mutations, the CDK6 protein not only affects cell cycle progression but also transcriptionally regulates oncogenic kinases mediating intrinsic drug resistance, including AURORA and AKT-a feature not shared by its homolog CDK4. While AKT and AURORA kinase inhibitors have significant therapeutic potential in AML, single agent activity has not been proven overly effective. We describe synergistic combination effects when applying these drugs together with palbociclib which could be readily translated to patients with AML bearing FLT3⁻ITD or ⁻TKD mutations. Targeting synergistically acting vulnerabilities, with CDK6 being the common denominator, may represent a promising strategy to improve AML patient responses and to reduce the incidence of selection of resistance-inducing mutations.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 D835Y	acute myeloid leukemia	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, patient-derived acute myeloid leukemia cells harboring FLT3 D835Y were sensitive to treatment with Ibrance (palbociclib) in culture, demonstrating reduced cell viability and colony formation (PMID: 30544932).	30544932
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Alisertib + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Ibrance (palbociclib) and Alisertib (MLN8237) resulted in a synergistic effect in acute myeloid leukemia cells expressing a FLT3-ITD, demonstrating a greater reduced cell viability compared to either agent alone (PMID: 30544932).	30544932
FLT3 exon 14 ins	hematologic cancer	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3 ITD were sensitive to treatment with Ibrance (palbociclib), demonstrating inhibition of cell growth in culture (PMID: 30544932).	30544932
FLT3 D835Y	hematologic cancer	sensitive	Everolimus + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Ibrance (palbociclib) and Afinitor (everolimus) resulted in a synergistic effect in transformed cells expressing FLT3 D835Y, demonstrating a greater reduced cell viability compared to either agent alone (PMID: 30544932).	30544932
FLT3 exon 14 ins FLT3 D835Y	hematologic cancer	no benefit	Danusertib + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing FLT3 ITD and FLT3 D835Y did not respond to the combination treatment of Ibrance (palbociclib) and Danusertib (PHA-739358) in culture (PMID: 30544932).	30544932
FLT3 exon 14 ins FLT3 D835Y	hematologic cancer	no benefit	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing FLT3 ITD and FLT3 D835Y did not respond to treatment with Ibrance (palbociclib) in culture (PMID: 30544932).	30544932
FLT3 D835Y	hematologic cancer	sensitive	Alisertib + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination treatment of Ibrance (palbociclib) and Alisertib (MLN8237) resulted in a synergistic effect in transformed cells expressing FLT3 D835Y, demonstrating a greater reduction in cell viability compared to either agent alone (PMID: 30544932).	30544932
FLT3 D835Y	hematologic cancer	sensitive	Palbociclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, transformed cells expressing FLT3 D835Y were sensitive to treatment with Ibrance (palbociclib), demonstrating reduced cell viability in culture and tumor growth inhibition in cell line xenograft models (PMID: 30544932).	30544932
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Ipatasertib + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Ibrance (palbociclib) and Ipatasertib (GDC-0068) resulted in a synergistic effect in acute myeloid leukemia cells expressing a FLT3-ITD, demonstrating a greater reduced cell viability compared to either agent alone (PMID: 30544932).	30544932
FLT3 D835Y	hematologic cancer	sensitive	Danusertib + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Ibrance (palbociclib) and Danusertib (PHA-739358) resulted in a synergistic effect, leading to a greater decrease in cell viability of transformed cells expressing FLT3 D835Y in culture compared to either agent alone (PMID: 30544932).	30544932
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	MK2206 + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Ibrance (palbociclib) and MK2206 resulted in a synergistic effect in acute myeloid leukemia cells expressing a FLT3-ITD, demonstrating a greater reduced cell viability compared to either agent alone (PMID: 30544932).	30544932
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	CCT137690 + Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Ibrance (palbociclib) and CCT137690 resulted in a synergistic effect in acute myeloid leukemia cells harboring a FLT3-ITD, demonstrating a greater reduced cell viability compared to either agent alone (PMID: 30544932).	30544932