Abstract
An international team of collaborating scientists has shown how the bone marrow microenvironment (BMM) can give leukemia cells with insufficient BRCA1 and BRCA2 gene expression the ability to resist PARP inhibitor anticancer drugs. The new study, published in Cell Reports, is claimed to be the first to show that this resistance to PARP inhibitors in leukemia can be overcome by combining PARP inhibition with drugs that block TGFβR kinase activation.
“Leukemia cells usually reside in two environments in the body, the bone marrow and the blood,” explains senior investigator Tomasz Skorski, M.D., Ph.D., DSc, professor of microbiology and immunology, Lewis Katz School of Medicine (LKSOM) at Temple University. “Previous research has shown that leukemia cells displaying deficiency of BRCA1 and BRCA2 proteins are sensitive to PARP inhibition while circulating in the blood. We discovered that the same leukemia cells are resistant to the inhibitors in the bone marrow microenvironment.”
PARP inhibitors trigger a phenomenon known as synthetic lethality in cancer cells. They kill malignant cells by shutting down a specific DNA repair mechanism and are especially effective against cells with BRCA1 and BRCA2 gene mutations, in which the homologous recombination mechanism of DNA repair has already been disabled.
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