Reference Detail

Ref Type

Journal Article

PMID

(27099147)

Authors

Uras IZ, Walter GJ, Scheicher R, Bellutti F, Prchal-Murphy M, Tigan AS, Valent P, Heidel FH, Kubicek S, Scholl C, Fröhling S, Sexl V

Title

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	127	23	2016 Jun 09	2890-902	Blood

URL

Abstract Text

Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.

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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
TCS 359		TCS-359\|TCS359	FLT3 Inhibitor 69	TCS 359 is a FLT3 inhibitor, which may inhibit the proliferation of cancer cells (PMID: 16580199, PMID: 27099147).

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 wild-type	acute myeloid leukemia	sensitive	Palbociclib	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) inhibited growth of human FLT3 wild-type human leukemia cells in culture (PMID: 27099147).	27099147
FLT3 wild-type	acute myeloid leukemia	sensitive	TCS 359	Preclinical	Actionable	In a preclinical study, TCS-359 inhibited growth of FLT3 wild-type acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	Palbociclib + Quizartinib	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) and Vanflyta (quizartinib) were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 wild-type	acute myeloid leukemia	sensitive	Palbociclib + TCS 359	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) following TCS-359 treatment enhanced growth inhibition of FLT3 wild-type acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	Palbociclib + Tandutinib	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) and tandutinib (MLN518) were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	Palbociclib + TCS 359	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) following TCS-359 treatment enhanced growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	TCS 359	Preclinical	Actionable	In a preclinical study, TCS-359 inhibited growth of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	Palbociclib	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) blocked growth, induced apoptosis, and inhibited STAT activation in human FLT3-ITD positive human acute myeloid leukemia cells in culture (PMID: 27099147).	27099147
FLT3 act mut	acute myeloid leukemia	sensitive	Palbociclib + SGI-1776	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) and SGI-1776 were synergistic towards growth inhibition of FLT3-ITD positive acute myeloid leukemia cell lines in culture (PMID: 27099147).	27099147