Current treatment strategies for inhibiting mTOR in cancer

Chiarini, Francesca; Evangelisti, Camilla; McCubrey, James A.; Martelli, Alberto M.

doi:10.1016/j.tips.2014.11.004

Cited by 230 publications

(185 citation statements)

References 110 publications

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“…Currently, mTOR inhibitors are under investigation in clinical studies as anticancer agents and are showing growth-inhibiting effects in preclinical models, including xenografts of HPV-positive cancer cells (41)(42)(43). The antitumorigenic effects of mTOR inhibitors in the clinic have often been unsatisfying when given as a monotherapy, however (44,45). Increasingly, mTOR inhibitors are being used in combination with CT, to sensitize tumor cells toward chemotherapeutic agents (46).…”

Section: Discussionmentioning

confidence: 99%

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Hoppe‐Seyler

Bossler

Lohrey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

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Oncogenic human papillomaviruses (HPVs) are closely linked to major human malignancies, including cervical and head and neck cancers. It is widely assumed that HPV-positive cancer cells are under selection pressure to continuously express the viral E6/E7 oncogenes, that their intracellular p53 levels are reconstituted on E6/E7 repression, and that E6/E7 inhibition phenotypically results in cellular senescence. Here we show that hypoxic conditions, as are often found in subregions of cervical and head and neck cancers, enable HPV-positive cancer cells to escape from these regulatory principles: E6/E7 is efficiently repressed, yet, p53 levels do not increase. Moreover, E6/E7 repression under hypoxia does not result in cellular senescence, owing to hypoxiaassociated impaired mechanistic target of rapamycin (mTOR) signaling via the inhibitory REDD1/TSC2 axis. Instead, a reversible growth arrest is induced that can be overcome by reoxygenation. Impairment of mTOR signaling also interfered with the senescence response of hypoxic HPV-positive cancer cells toward prosenescent chemotherapy in vitro. Collectively, these findings indicate that hypoxic HPV-positive cancer cells can induce a reversible state of dormancy, with decreased viral antigen synthesis and increased therapeutic resistance, and may serve as reservoirs for tumor recurrence on reoxygenation.human papillomavirus | tumor virus | cervical cancer | hypoxia | mTOR O ncogenic human papilloma viruses (HPVs) are some of the most important known cancer risk factors and are closely linked to the development of every 20th human cancer worldwide, including prevalent cancers in the oropharynx and anogenital region (1, 2). Best characterized is their causative role for cervical cancer, which alone accounts for more than 500,000 new cancer cases and more than 250,000 cancer deaths per year worldwide (3). Cervical cancer cells virtually always contain the DNA of high-risk HPV types, such as HPV16 and HPV18. Maintenance of the malignant phenotype of HPV-positive cancer cells is considered to require sustained expression of the viral E6/E7 oncogenes (1, 2). Inhibition of E6/E7 expression leads to the rapid induction of cellular senescence (4-6), a central tumorsuppressive pathway, resulting in an irreversible growth arrest (7). This indicates that the viral oncogenes maintain the growth of HPV-positive cancer cells by blocking cellular senescence. However, their potential to induce senescence on E6/E7 inhibition also shows that this pathway is not irreversibly destroyed in HPV-positive cancer cells.These considerations are not only fundamental for our mechanistic concepts of HPV-linked cell transformation, but also have important therapeutic implications. The development of specific E6/E7 inhibitors could provide a rational strategy for targeting HPV-positive neoplasias (8, 9) as a tumor-specific prosenescence therapy (10, 11). Furthermore, the concept that continuous E6/E7 expression is essential for the growth of HPV-positive tumor cells implies that the two viral prote...

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Section: Discussionmentioning

confidence: 99%

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Hoppe‐Seyler

Bossler

Lohrey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

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“…Indeed, a recent clinical study suggests that a rapalog everolimus is able to reduce immunosenescence in elderly people (Mannick et al, 2014). Results in cancer therapy have been disappointing (Chiarini et al, 2015), and this may reflect the fact that blocking mTOR, which reduces S6K activation, results in blocking of a feedback inhibitory loop that results in PI3K-Akt activation in malignant cells. The reduction in autophagy by rapamycin may also work against the killing of malignant cells.…”

Section: B Inhibiting Phosphoinositide-3-kinase-aktmammalian Target mentioning

confidence: 99%

“…This has suggested that dual inhibitors of PI3K and mTOR may be more beneficial, because this avoids the PI3K-Akt feedback loop. There is close structural homology between these kinases, and several dual inhibitors have been developed and are now in clinical trials (Chiarini et al, 2015). None of these treatments has so far been tested in airway disease.…”

Section: B Inhibiting Phosphoinositide-3-kinase-aktmammalian Target mentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

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“…It is stimulated by branched chain amino acids through the RAS-related GTP-binding proteins, (RAG) family of GTPases, which recruit mTORC1 to lysosomes where it becomes activated by Rheb. mTORC1 phosphorylates unc-51 like autophagy activated kinase (ULK1) and its positive regulator, autophagy-related protein 13 (ATG13), inhibiting autophagosome formation [67,75,76]. Signaling pathways involving mTORC1 are complex, and there are many negative loops which add a further level of regulation.…”

Section: Mtormentioning

confidence: 99%

Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers

Lineham

Spencer

Morley

2017

Future Medicinal Chemistry

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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Current treatment strategies for inhibiting mTOR in cancer

Cited by 230 publications

References 110 publications

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers

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