Enhancing Mammalian Target of Rapamycin (mTOR)–Targeted Cancer Therapy by Preventing mTOR/Raptor Inhibition-Initiated, mTOR/Rictor-Independent Akt Activation

Wang, Xuerong; Yue, Ping; Kim, Young Ae; Fu, Haian; Khuri, Fadlo R.; Sun, Shi‐Yong

doi:10.1158/0008-5472.can-08-1522

Cited by 148 publications

(195 citation statements)

References 28 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…In addition, mTORC1 knockdown with raptor siRNA did not block rapamycin-induced Akt phosphorylation in DLBCL cells. This finding is in contrast with the studies in lung cancer cells where rapamycin increased Akt phosphorylation independent of mTORC2 32 and consistent with the results of others in different For personal use only. on May 10, 2018. by guest www.bloodjournal.org From model systems.…”

Section: Discussionsupporting

confidence: 91%

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

Gupta

Ansell

Novak

et al. 2009

Blood

150

161

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 91%

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

Gupta

Ansell

Novak

et al. 2009

Blood

150

161

View full text Add to dashboard Cite

show abstract

“…Similar to our results, transient disruption of the mTORC1 complex in human lung cancer cells resulted in increased phosphorylation of Akt S473 without a detectable effect on S6K1 phosphorylation confirming that these 2 events are not always concurrent. 49 Our results clearly indicate a role for Mer in mTOR-mediated feedback inhibition of Akt. Mer may also play a role in regulation of mTOR activity.…”

Section: Discussionmentioning

confidence: 54%

Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia

Linger¹,

DeRyckere²,

Brandão³

et al. 2009

Blood

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 80%. However, additional changes using available drugs are unlikely to provide significant improvement in survival. New therapies are warranted given the risk of severe therapy-associated toxicities including infertility, organ damage, and secondary malignancy. Here, we report ectopic expression of the receptor tyrosine kinase Mer in pediatric B-cell ALL. Inhibition of Mer prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, we discovered cross-talk between the Mer and mammalian target of rapamycin (mTOR) signaling pathways. Our results identify Mer as a novel therapeutic target in ALL and suggest that inhibitors of Mer will interact synergistically with currently used therapies. This strategy may allow for dose reduction resulting in decreased toxicity and increased survival rates. Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

show abstract

“…In some other studies using EBV-positive B cell lines (21) or other cell lines (36,37), inhibition of 4E-BP1 phosphorylation by rapamycin was partial, whereas inhibition of p70S6K phosphorylation was complete. The reason is uncertain, but activation of survival signaling pathways such as Akt may prevent complete inhibition of 4E-BP1 phosphorylation (37). It has been shown that rapamycin induces Akt activation through an mTOR complex, resulting in the attenuating growth-inhibitory effect of rapamycin (37).…”

Section: Discussionmentioning

confidence: 90%

mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein–Barr Virus–Associated T and Natural Killer Cell Lymphoma Cells

Kawada

Ito

Iwata

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Epstein-Barr virus (EBV) infects B cells, as well as T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells, mTOR performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBVassociated T-and NK-cell lymphomas.Experimental Design: We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T-and NK-cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3, and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analogue, CCI-779) against these cell lines in culture and in a murine xenograft model that was established by subcutaneous injection of SNK6 cells into NOG mice.Results: All EBV-positive and -negative T-and NK-cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors induced G 1 cellcycle arrest and inhibited cell proliferation in T-and NK-cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and -negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood.Conclusion: These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T-and NK-cell lymphoma. Clin Cancer Res; 20(21); 5412-22. Ó2014 AACR.

show abstract

Enhancing Mammalian Target of Rapamycin (mTOR)–Targeted Cancer Therapy by Preventing mTOR/Raptor Inhibition-Initiated, mTOR/Rictor-Independent Akt Activation

Cited by 148 publications

References 28 publications

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

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

Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia

mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein–Barr Virus–Associated T and Natural Killer Cell Lymphoma Cells

Contact Info

Product

Resources

About