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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2075-2083.
Prepublished online as a Blood First Edition Paper on May 30, 2007; DOI 10.1182/blood-2007-02-071266.
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Submitted February 1, 2007
Accepted May 24, 2007
Pharmacologic inhibition of CDK4/6 : mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia
Lisheng Wang, Jie Wang, Bradley W. Blaser, Anne-Marie Duchemin, Donna F. Kusewitt, Tom Liu, Michael A. Caligiuri, and Roger Briesewitz*
Department of Pharmacology, The Ohio State University, Columbus, OH, United States
Departments of Internal Medicine, and the Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, United States
Department of Psychiatry, The Ohio State University, Columbus, OH, United States
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
* Corresponding author; email: roger.briesewitz{at}osumc.edu.
Entry into cell cycle is mediated by CDK4/6 activation, followed by CDK2 activation. We found that pharmacological inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in AML patients, led to the downregulation of Cyclin D2 and D3 followed by pRb dephosphorylation and G1 cell cycle arrest. This implicated the D-Cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single agent PD 0332991, a selective CDK4/6 inhibitor, caused sustained cell cycle arrest in Flt3 ITD AML cell lines, and prolonged survival in an in vivo model of Flt3 ITD AML. PD 0332991 caused an initial cell cycle arrest in well-established Flt3 wildtype (wt) AML cell lines, but this was overcome by downregulation of p27Kip and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt primary AML patient sample. In summary, the mechanism of cell cycle arrest following treatment of Flt3 ITD AML with a FLT3 inhibitor involves downregulation of Cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML, but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation of CDK2.
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