Tumor Drug Resistance Helps Identify a Novel Therapy for Leukemia
By Sahana Shankar, Ph.D. Candidate
A wide variety of leukemias are treated with a broad spectrum of cytotoxic drugs. Tyrosine kinase inhibitors (TKi) are broadly used as anti-cancer drugs since many tumors result in the expression of Oncogenic tyrosine kinases (OTKs). However, the efficiency of TKi is not uniform for all leukemias and complete remissions are rare. A possible explanation is that OTK+ tumor cells can repair spontaneous and drug-induced DNA changes that alter/enhance their survival as compared to normal cells.
The two main repair mechanisms in cells are Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ). PARP1 is an effector protein in the NHEJ pathway which works both in proliferating and quiescent cells. PARP1 inhibitors (PARPi) are a class of drugs that trigger synthetic lethality to suppress DNA repair and attack tumor cells. However, some tumor cells can develop resistance to PARP1 inhibitors, due to a loss of PARP1 expression and other factors.
A collaborative study from scientists at the Lewis Katz School of Medicine at Temple University (LKSOM), Polish Academy of Sciences, Washington University School of Medicine, Saint Louis, Fox Chase Cancer Center, Medical University of Vienna, and Ludwig-Boltzmann Institute for Hematology, Memorial Sloan Kettering Cancer Center, New York, among others, show that it is the microenvironment at the bone marrow which controls the DNA repairing ability of leukemia cells and their resistance to PARPi.
Leukemia cells are usually found in peripheral blood and hematopoietic tissues such as bone marrow and spleen. Blood and tissue differ in their ‘microenvironment’- a combination of cells and extracellular signals which maintain the ability to protect and nourish. The microenvironment is an important factor for tumor progression. In leukemia, the bone marrow microenvironment is modulated to promote tumor cell survival by conferring resistance against TKi and cytotoxic drugs. In this study, the authors compared the peripheral blood and bone marrow microenvironments in their ability to promote DNA damage repair in a wide range of leukemias via TGFß receptor kinase signaling.
In a laboratory screen of multiple leukemias to resist PARP1-mediated toxicity, the authors found that leukemia cells in bone marrow microenvironments (BMM), especially those with BRCA1 and BRCA2 deficiency, were protected from the toxic effect of PARP1 inhibitor, olaparib. Analyzing the bone marrow remodeling for the production of cytokines, they found an increased expression of TGF-ß1 and its receptor, TGF-ß1R in stromal cells of the bone marrow and downstream activation of SMAD.
To establish direct evidence, the authors removed TGFß or its receptors in various cell lines and found enhanced sensitivity of tumor cells to olaparib. Conversely, activation of the TGFßR kinase pathway induced resistance to olaparib. Further studies showed that leukemia cells were resistant to TKi+PARPi treatment in BMM and sensitivity was restored upon inhibition of the TGFß pathway. The BMM also contributed to promoting quiescence in leukemia cells which could also explain the drug resistance.
A combination of TGFß inhibition with TKi and PARPi in the mouse model of leukemia showed enhanced anti-leukemia effect and prolonged survival. The authors confirmed that the TGFß pathway is important for DNA repair since inhibition of the TGFß kinase resulted in increased accumulation of DNA double-stranded breaks in leukemia cells in BMM. SMAD3 inhibitor-induced drug sensitivity, indicating that SMAD is the downstream ligand of the TGFß pathway which regulates DNA repair. This study unravels a new pathway for attacking leukemia cells, by preventing drug resistance and enhanced efficacy.
“We’ve now discovered a central and constitutive mechanism underlying PARP drug resistance in leukemia,” senior investigator, Dr. Tomasz Skorski said. “And we went a step further, showing that resistance can be overcome through a therapeutic strategy that combines inhibitors targeting PARP and TGFßR kinase. The drugs we experimented within our latest research are already approved for use in patients,” he noted. “We look forward to future collaborations that will allow us to translate our findings on combined PARP and TGFßR kinase inhibitor therapy to the clinic.”
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