Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma?

Tarantelli, Chiara; Lupia, Antonio; Stathis, Anastasios; Bertoni, Francesco

doi:10.3390/ijms21031060

Cited by 31 publications

(25 citation statements)

References 153 publications

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“…Here, we applied this approach to determine whether post-transcriptional regulation mediated by lncRNAs might be an additional layer to quickly control protein expression in diffuse large B cell lymphoma (DLBCL) cells exposed to bimiralisib, a dual PI3K/mTOR inhibitor with proven preclinical and early clinical anti-lymphoma activity [ 8 , 9 ]. The mTOR pathway regulates cell growth and proliferation in response to mitogen, nutrient, and energy status and therefore controls the balance between anabolism and catabolism in response to environmental conditions [ 10 , 11 , 12 ]. In addition to various anabolic processes as protein, lipid and nucleotide synthesis, mTOR also promotes cell growth by suppressing protein catabolism.…”

Section: Introductionmentioning

confidence: 99%

Exon–Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation

Munz

Cascione

Parmigiani

et al. 2021

ncRNA

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Stressful conditions induce the cell to save energy and activate a rescue program modulated by mammalian target of rapamycin (mTOR). Along with transcriptional and translational regulation, the cell relies also on post-transcriptional modulation to quickly adapt the translation of essential proteins. MicroRNAs play an important role in the regulation of protein translation, and their availability is tightly regulated by RNA competing mechanisms often mediated by long noncoding RNAs (lncRNAs). In our paper, we simulated the response to growth adverse condition by bimiralisib, a dual PI3K/mTOR inhibitor, in diffuse large B cell lymphoma cell lines, and we studied post-transcriptional regulation by the differential analysis of exonic and intronic RNA expression. In particular, we observed the upregulation of a lncRNA, lncTNK2-2:1, which correlated with the stabilization of transcripts involved in the regulation of translation and DNA damage after bimiralisib treatment. We identified miR-21-3p as miRNA likely sponged by lncTNK2-2:1, with consequent stabilization of the mRNA of p53, which is a master regulator of cell growth in response to DNA damage.

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Section: Introductionmentioning

confidence: 99%

Exon–Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation

Munz

Cascione

Parmigiani

et al. 2021

ncRNA

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“…As DNA-PK belong to the PI3K family subgroup along with ATR and ATM kinases [148], the first inhibitors were directed against the ATP pocket, which is not specific for DNA-PK. Hence, they could inhibit multiple kinases and sensitize different tumor types, including lymphoma and CLL cells, to chemotherapeutic agents and IR [65,68,149]. CC-115 is a dual DNA-PK and TORC1/TORC2 inhibitor with pre-clinical and early clinical activity in CLL [150,151].…”

Section: Dna-pk Inhibitorsmentioning

confidence: 99%

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Carrassa¹,

Colombo

Damia

et al. 2020

Cancer Treatment Reviews

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The DNA damage response (DDR) is a well-coordinated cellular network activated by DNA damage. The unravelling of the key players in DDR, their specific inactivation in different tumor types and the synthesis of specific chemical inhibitors of DDR represent a new hot topic in cancer therapy. In this article, we will review the importance of DDR in lymphoma development and how this can be exploited therapeutically. Specifically, we will focus on CHK1, WEE1, ATR, DNA-PK and PARP inhibitors, for which preclinical data as single agents or in combination has been accumulating, fostering their clinical development. The few available clinical data on these inhibitors will also be discussed.

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“…There is also strong evidence that simultaneous PI3K/mTOR inhibition induces better preclinical antitumor activity than single targeting in lymphoma [ 156 ]. Several PI3K/mTOR dual inhibitors have been developed in recent years, also thanks to a good structural similarity between the two kinases [ 157 ]. One such compound, bimiralisib (PQR309; Figure 7 ), was shown to inhibit all class I PI3K catalytic enzymes and mTOR with low nanomolar potency selectively while sparing the rest of the kinome [ 158 ].…”

Section: Introductionmentioning

confidence: 99%

Dual Kinase Targeting in Leukemia

Mologni

Marzaro

Zambon

2021

Cancers

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Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and lymphoid tumors, giving details on preclinical studies as well as ongoing clinical trials. A brief overview of dual-targeting inhibitors (kinase/histone deacetylase (HDAC) and kinase/tubulin polymerization inhibitors) applied to leukemia is also given. Finally, the very recently developed Proteolysis Targeting Chimeras (PROTAC)-based kinase inhibitors are presented.

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Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma?

Cited by 31 publications

References 153 publications

Exon–Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation

Exon–Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Dual Kinase Targeting in Leukemia

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