22 May Breast Cancer Drug May Also Treat Aggressive Leukemia
MedicalResearch.com Interview with:
Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl
Institute of Pharmacology and Toxicology
University of Veterinary Medicine
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Patients suffering from AML have poor prognosis and high mortality rate despite considerable advances in chemotherapy and hematopoietic stem cell transplantations. Up to 30% of patients with AML harbor an activating mutation in the FLT3 receptor tyrosine kinase (FLT3-ITD). Such mutations are associated with a high predisposition to relapse after remission. In a simplified way we can say that these tumor cells depend on FLT3: Is FLT3 blocked, cells die. Hence, FLT3 inhibitors are being developed as targeted therapy for FLT3-mutant AML; however, clinical responses are short-lived and their use is complicated by rapid development of resistance. This emphasizes the need for additional therapeutic targets.
Our study represents a novel therapeutic window to specifically target and kill AML cells with FLT3-ITD mutations. We found that the tumor-promoting enzyme CDK6 but not its close relative CDK4 directly regulates and initiates the production/transcription of FLT3 and thus lead to disease. The FDA-approved kinase inhibitor Palbociclib not only blocks the activity of CDK6 but in turn impairs FLT3 expression: Mutant AML cells die immediately. The treatment does not affect cells without the mutation.
The power of CDK6 inhibition in AML cells goes beyond FLT3: Palbociclib also stops production of the PIM1 kinase and thus overcomes the potential activation of survival pathways counteracting the effects of FLT3 inhibition.
MedicalResearch.com: What should readers take away from your report?
Response: In 2015, Palbociclib has received full FDA approval to treat breast cancer. We now show that Palbociclib also offers a therapeutic breakthrough in patients suffering from FLT3-driven AML. Leukemic cells are attacked in a dual way: CDK6 inhibition impairs the production of FLT3 and PIM1, and thus deprive cells of “nutrients”.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: This study has immediate clinical relevance: A clinical trial in FLT3-driven AML needs to be initiated. Furthermore, this is the first study that shows that the transcriptional activity of CDK6 depends on its kinase activity. In this way the CDK6 inhibitor attacks two birds with one stone: It not only lessens cell proliferation but also destroys the Achilles’ heel of a cancer cell. Kinase-dependent and -independent functions of CDK6 need to be carefully dissected also in other cancer entities to a greater extent which shall give rise to further efficacious target-specific agents for leukemia.
MedicalResearch.com: Is there anything else you would like to add?
Response: Our study may also offer a direct influence for clinical decisions in other diseases: FLT3 mutations are not restricted to AML but are also detected in patients suffering from chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and acute lymphoid leukemia (ALL). Furthermore, many patients with AML and ALL express high levels of wildtype FLT3. We showed that simultaneously targeting CDK6 and FLT3 is highly effective in killing the FLT3-wildtype leukemic cells while respective mono-therapies fail to do so. Such a synergy might be the key overcome potential resistance to treatment and enable lower doses of the drugs to be used, minimizing toxicities while maintaining therapeutic efficacy.
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Iris Z. Uras, Gina J. Walter, Ruth Scheicher, Florian Bellutti, Michaela Prchal-Murphy, Anca S. Tigan, Peter Valent, Florian H. Heidel, Stefan Kubicek, Claudia Scholl, Stefan Fröhling, and Veronika Sexl. Palbociclib treatment of FLT3-ITD AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood, 2016
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