A New Leukemia PARPi Resistance Mechanism Revealed

Significance 

Leukemia cells usually reside in two environments in the body, the bone marrow and the blood. Previous research has shown that leukemia cells displaying deficiency of BRCA1 and BRCA2 proteins are sensitive to PARP inhibition while circulating in the blood. The authors discovered that the same leukemia cells are resistant to the inhibitors in the bone marrow microenvironment.

An international research team led by Professor Tomasz at Temple University has shown how the bone marrow microenvironment can give leukemia cells with insufficient BRCA1 and BRCA2 gene expression the ability to resist PARP inhibitor (PARPi) 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 TGFßR kinase activation.

The mix of cells and fluids immediately surrounding human bone marrow provides critical protective and nourishing conditions for bone marrow-originating hematopoietic stem cells. Immune cells and other specialized components native to this small-scale microenvironment ensure that newly emerged hematopoietic stem cells are healthy and functional. Despite this protection, the bone marrow microenvironment is vulnerable to manipulation. In the case of blood cancer leukemia, for example, the bone marrow niche is modulated to protect and promote the survival of tumor cells.

The research team have now shown that this protective microenvironment also gives leukemia cells with insufficient expression of BRCA1 and BRCA2 genes the ability to resist anticancer drugs known as PARP inhibitors. This resistance, the researchers discovered, hinges on overexpression of transforming growth factor beta receptor (TGFßR) kinase, which is located on the leukemia cell surface.  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.

Although BRCA1/2 mutations are rare in hematological malignancies, the team noted, myeloid and lymphoid malignancies display specific defects in DSB [double strand break] repair, which are susceptible to synthetic lethality triggered by PARPi. But while such synthetic lethality triggered by PARP inhibitors has yielded “promising therapeutic results. unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break end resection regulation.

They investigated the mechanistic impact of the bone marrow microenvironment on PARP inhibitor resistance in BRCA1/2-deficient leukemia cells derived from human patients, and leukemia-bearing mice. The cells were grown in incubation conditions that mimicked the bone marrow microenvironment, enabling the malignant cells to establish drug resistance. Examination of factors in the replicated bone marrow microenvironment identified TGF-ß1 as an important player in resistance. TGF-ß1, a protein generated by stromal cells in the bone marrow niche, activates TGFßR kinase. Leukemia cells in the bone marrow microenvironment were found to be highly responsive to TGF-ß1, relating to the low oxygen levels that induce overexpression of TGFßR kinase on their surface.

With TGFßR kinase levels noticeably elevated in leukemia cells, the researchers turned to testing any potential effects of TGFßR kinase inhibition. They observed that treatment with molecules that blocked TGFßR kinase activation by TGF-ß1 not only halted signaling along the TGF-ß1-TGFßR kinase axis, but also rendered cells sensitive to PARP inhibitors.

Those observations could be replicated in animals, where targeting of the TGFßR kinase restored leukemia cell sensitivity to PARP inhibitors. Leukemia-bearing mice treated with a PARP inhibitor plus a TGFßR kinase inhibitor also survived longer than did mice treated only with PARP inhibition. “In summary, we identified an unexpected mechanism of resistance to PARPi, which depends on the TGF-ß1 -mediated activation of TGFßR kinase intracellular signaling in leukemia cells in bone marrow.  It is likely that not only leukemia cells but also solid tumor cells metastatic to BM may be protected from PARPi-mediated synthetic lethality.

Skorski and his colleagues now discovered a central and constitutive mechanism underlying PARP drug resistance in leukemia. And went a step further, showing that resistance can be overcome through a therapeutic strategy that combines inhibitors targeting PARP and TGFßR kinase.

The researchers plan next to investigate this strategy clinically, and suggest the same dual therapy approach may also be feasible in some patients with solid tumors. They postulate that the pharmacological targeting of the TGFßR kinase can improve therapeutic outcomes in leukemic patients receiving PARPis and other drugs, whose activities are limited in the BM niche due to enhanced DSB repair. A similar approach may also be applied to treat solid tumors. In addition, tumors carrying TGFBR2 deletions/mutations should be responsive to PARPi in the BMM. The drugs we experimented with in our latest research are already approved for use in patients

A New Leukemia PARPi Resistance Mechanism Revealed - Medicine Innovates

Reference

Bac Viet Le, Paulina Podszywalow-Bartnicka, Silvia Maifrede, Mariusz A. Wasik, Katarzyna Piwocka, Tomasz Skorski. TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment. Cell Reports. volume 33, issue 1, 108221, October 06, 2020

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