The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage
response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic
target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC
oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL
patients, we found that about half of DLBCLs showed constitutive expression of the
phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and
of phosphorylated histone H2AX (γH2AX), marker of DNA damage and genomic instability.
Constitutive γH2AX expression correlated with c-MYC levels and DDR activation, and defined a
subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as
a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic
approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in
DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a
different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage
accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that
pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel
therapeutic strategy in DLBCL.
The second part of this work is the clinical, molecular and functional description of a paradigmatic
case of primary refractory Burkitt lymphoma characterized by spatial intratumor heterogeneity for
the TP53 mutational status, high expression levels of genomic instability and DDR activation
markers, primary resistance to chemotherapy and exquisite sensitivity to DDR inhibitors.
| Identifer | oai:union.ndltd.org:unibo.it/oai:amsdottorato.cib.unibo.it:6752 |
| Date | 22 January 2015 |
| Creators | Derenzini, Enrico <1978> |
| Contributors | Pileri, Stefano |
| Publisher | Alma Mater Studiorum - Università di Bologna |
| Source Sets | Università di Bologna |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, PeerReviewed |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
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