Phospho-p70s6k and cdc2/cdk1 Are Associated with Diffuse Large B-Cell Lymphoma and Are Potential Targets for Combination Chemotherapy
MY Zhao, A Auerbach, A DCosta, AP Rapoport, AM Burger, F Jiang, SA Stass, AK Sands, N Aguilera, EA Sausville, XF Zhao. University of Maryland School of Medicine, Baltimore, MD; Armed Forces Institute of Pathology, Washington, DC; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD; University at Buffalo, SUNY, Buffalo, NY
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults. However, only 40-60% of the DLBCL patients respond to the current standard therapy and recurrence after the initial remission is quite common. This study was to identify and evaluate novel molecular targets for the development of novel combination chemotherapy to treat the refractory and recurrent DLBCL.
Design: Lymphoma samples from 38 cases of primary and recurrent DLBCL were analyzed using real time quantitative PCR of the RPS6KB1 and CDC2 genes, and immunohistochemistry for their gene products p70S6K/p85S6K and cdc2/cdk1. The Farage, Karpas422, Pfeiffer and Toledo DLBCL cell lines were subsequently treated with combined rapamycin and UCN-01. The cell proliferation, apoptosis and cell cycle progression were analyzed after the drug treatment. Several key protein kinases involved in the PI3K/Akt/mTOR pathway, apoptosis and cell cycle progression were analyzed after the drug treatment.
Results: Amplification of RPS6KB1 and CDC2 genes was found in both primary and recurrent DLBCL. Moreover, the vast majority of these lymphomas (94%) were strongly positive for phospho-p70S6K and cdc2/cdk1 proteins. Combination of rapamycin and UCN-01 (R+U) synergistically inhibited the DLBCL cell proliferation by inducing G1 arrest as well as apoptosis of the DLBCL cells through suppressing the phosphorylation of p70S6K/p85S6K and CDC2 expression.
Conclusions: The RPS6KB1 and CDC2 overexpression is common in DLBCL. Simultaneously targeting the RPS6KB1 and CDC2 products phospho-p70S6K/p85S6K and cdc2/cdk1 is very effective in inhibiting DLBCL proliferation and overcoming drug resistance. This work suggests that multi-level inhibition of PI3K/Akt/mTOR pathway and double block of cell cycle progression are effective strategies for the DLBCL combination chemotherapy.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 174, Wednesday Morning