Abstract
LMO2 expression correlated with increased response to olaparib and olaparib with R-CHOP.
Major Finding: LMO2 expression correlated with increased response to olaparib and olaparib with R-CHOP.
Mechanism: LMO2-mediated homologous recombination defects increased DNA double-strand breaks in highly LMO2-expressing cells.
Impact: Clinical trials of PARP inhibitors in patients with highly LMO2-expressing cancers are warranted.
High expression of LIM-domain only 2 (LMO2) is one of the strongest biomarkers predicting longer survival in diffuse large B-cell lymphomas (DLBCL), but the biological significance of LMO2 expression is not known. Parvin, Ramirez-Labrada, and colleagues found that patient-derived DLBCLs and DLBCL lines that highly express LMO2 protein had increased DNA double-strand breaks (DSB). Induction of high LMO2 expression in DLBCL lines with low LMO2 expression led to an increase in DNA DSBs, whereas LMO2 knockdown in lines with higher LMO2 expression caused a decrease in DNA DSBs. LMO2 protein expression caused deficiencies in homologous recombination (HR)–based DSB repair mechanisms; for example, LMO2 protein expression reduced BRCA1- and RAD51-associated DNA-damage foci. LMO2 appeared to form a complex with the HR inhibitor 53BP1 at sites of HR-mediated DNA DSB repair, and 53BP1 was required for LMO2′s inhibition of HR. Treatment with the PARP inhibitor olaparib, which stalls replication-fork progression and triggers a DNA-damage response, led to a decrease in proliferation and an increase in apoptosis in DLBCL lines that highly expressed LMO2. This result was also noted in T-cell acute lymphoblastic leukemia (T-ALL) cell lines, hinting at the potential broader relevance of the finding. The reduced proliferation of highly LMO2-expressing DLBCL lines observed with olaparib was increased when the drug was given in combination with doxorubicin, and this was also the case in patient-derived DLBCL, follicular lymphoma, and T-ALL cells, consistent with the idea that high LMO2 levels inhibit HR-mediated DNA DSB repair. In mouse models of DLBCL using cell lines and patient-derived xenografts, response to treatment with olaparib was greatly increased in mice with tumors with high expression of LMO2, and response to treatment with olaparib combined with standard R-CHOP immunochemotherapy was greater than the response to either agent alone. Collectively, these results suggest that clinical trials of PARP inhibitors in highly LMO2-expressing cancers—which are not limited to DLBCL and include some breast and prostate cancers—may be fruitful.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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