Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2

Abstract

The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. IntroductionDiffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL), is the most common type of lymphoma in the United States. With rituximab-based chemoimmunotherapy such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, approximately 60% of DLBCL patients are cured. 1,2 Salvage chemotherapy followed by stem cell transplantation is able to produce durable remissions in a minority of relapsed patients, and improved therapy is required for those who relapse after second-line treatment.Because deregulation of the PI3 kinase (PI3K)/mTOR pathway occurs in many human diseases, 3,4 targeting the mTOR pathway with small molecule inhibitors has become an intense area of research. Key components of this pathway, including Akt and mTOR, regulate cell growth and survival. 5 The mTOR kinase exists as 2 complexes. The rapamycin-sensitive mTOR complex 1 (mTORC1 or raptor/mTOR), consists of mTOR, raptor, and mLST8. mTORC1 regulates translation initiation through 2 distinct pathways: ribosomal p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). In one pathway, mTORC1 phosphorylates and activates the ribosomal protein S6. In the second pathway, mTORC1 directly phosphorylates 4E-BP1 causing its dissociation from the translation initiation factor eIF4E. This allows eIF4E to stimulate cap-dependent RNA translation. In the absence of mTORC1 activation, 4EBP1 binds tightly to eIF4E, preventing it from binding to 5Ј-capped mRNA. 6 The mTOR complex 2 (mTORC2 or rictor/mTOR), which contains mTOR, rictor, and mLST8, is rapamycin insensitive and functions to regulate the survival kinase Akt by phosphorylation of serine 473. 5 Recent clinical trials of the mTORC1 inhibitors temsirolimus and everolimus, both analogues of the parent compound rapamycin, have demonstrated overall response rates (ORRs) of approximately 30% for relapsed DLBCL. 7 This single-agent activity of mTOR inhibitors in heavily pretreated DLBCL patients highlights the importance of the PI3K/mTOR pathway in these cells. To exploit the sensitivity of lymphomas to mTOR inhibitors through effective therapies, it is important to understand the mechanistic basis for resistance of DLBCL to mTOR inhibition.Histone deacetylase inhibitors (HDIs) have emerged as a potentially promising new class of anticancer drugs. The inhibition of histone deacetylases (HDACs) by HDIs results in increased gene-specific his...

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…Based on this work, rapalogs have been studied in preclinical models of DLBCL, finding considerable activity as a single agent and synergy with histone deacetylase inhibitors and rituximab. [194][195][196] These results have been validated in early-stage clinical trials in adults, finding single-agent ORR of 28-30%, using everolimus or temsirolimus. [197,198] Hodgkin's disease is a highly curable tumor in children; however, more aggressive or relapsed Hodgkin's disease can be difficult to treat.…”

Histone Deacetylase 3 Suppression Increases PH Domain and Leucine-rich Repeat Phosphatase (Phlpp)1 Expression in Chondrocytes to Suppress Akt Signaling and Matrix Secretion

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Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

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