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Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5-7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton's tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents., (Published by Elsevier Ltd.)

Purpose: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy., Experimental Design: We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting., Results: MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P < 0.001)., Conclusion: Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance., (©2011 AACR.)

Bortezomib induces remissions in 30%-50% of patients with relapsed mantle cell lymphoma (MCL). Conversely, more than half of patients' tumors are intrinsically resistant to bortezomib. The molecular mechanism of resistance has not been defined. We generated a model of bortezomib-adapted subclones of the MCL cell lines JEKO and HBL2 that were 40- to 80-fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling, we discovered that bortezomib resistance was associated with plasmacytic differentiation, including up-regulation of IRF4 and CD38 and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib-resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knockdown of IRF4 was toxic for the subset of MCL cells with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. This study has been registered at http://clinicaltrials.gov as NCT00131976.