Abstract:Growth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), initiating a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The PI3K/AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, including hematologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of leukemia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and TORC2. The majority… Show more
“…Otros medicamentos como los anticuerpos monoclonales se han estudiado en aquellos pacientes con marcadores como CD20+ y CD19+ 34 . Más recientemente los inhibidores de la vía mTOR (everolimus) se han vuelto una nueva opción en especial en los pacientes con leucemia linfoide T 35 . A pesar de estos avances alrededor del 60% de los pacientes presentará una recaída dentro de los primeros 2 años de tratamiento siendo el principal sitio la médula ósea contando con bajas tasas de segundas RC y aun una supervivencia pobre (24 semanas en promedio) 36 .…”
“…Otros medicamentos como los anticuerpos monoclonales se han estudiado en aquellos pacientes con marcadores como CD20+ y CD19+ 34 . Más recientemente los inhibidores de la vía mTOR (everolimus) se han vuelto una nueva opción en especial en los pacientes con leucemia linfoide T 35 . A pesar de estos avances alrededor del 60% de los pacientes presentará una recaída dentro de los primeros 2 años de tratamiento siendo el principal sitio la médula ósea contando con bajas tasas de segundas RC y aun una supervivencia pobre (24 semanas en promedio) 36 .…”
“…3F, lane 7). However, rapamycin, which is known to have little effect on the phosphorylation of 4E-BP1 (46,47), inhibited phosphorylation of 4E-BP1 only at a very high concentration (Fig. 3F, lanes 9 and 10).…”
Section: Hpv16 Psvs Induce Rapid Activation Of Akt In Hacat Cells Fullmentioning
The mammalian target of rapamycin (mTOR) downstream of phosphatidylinositol 3-kinase (PI3K) in the growth factor receptor (GFR) pathway is a crucial metabolic sensor that integrates growth factor signals in cells. We recently showed that human papillomavirus (HPV) type 16 exposure activates signaling from GFRs in human keratinocytes. Thus, we predicted that the virus would induce the PI3K/mTOR pathway upon interaction with host cells. We detected activation of Akt and mTOR several minutes following exposure of human keratinocytes to HPV type 16 (HPV16) pseudovirions. Activated mTOR induced phosphorylation of the mTOR complex 1 substrates 4E-BP1 and S6K, which led to induction of the functional protein translational machinery. Blockade of epidermal GFR (EGFR) signaling revealed that each of these events is at least partially dependent upon EGFR activation. Importantly, activation of PI3K/Akt/mTOR signaling inhibited autophagy in the early stages of virus-host cell interaction. Biochemical and genetic approaches revealed critical roles for mTOR activation and autophagy suppression in HPV16 early infection events. In summary, the HPV-host cell interaction stimulates the PI3K/Akt/mTOR pathway and inhibits autophagy, and in combination these events benefit virus infection.
“…With increasing knowledge and understanding of the role of the different TORC1 and TORC2 complexes in tumorigenesis, there has been substantial interest and extensive preclinical efforts to develop the next generation of mTOR inhibitors, with dual inhibitory activities against both TORC1 and TORC2 complexes [4,[108][109][110][111][112][113][114][115]. Such efforts are especially relevant with the emerging realization that the first class of inhibitors, the rapalogs, have so far shown significant clinical efficacy only against some relatively rare types of malignancies (RCC, pancreatic neuroendocrine tumors and mantle cell lymphoma), whereas major objective response rates are limited in more common solid tumors [116].…”
Section: Other Hematological Malignanciesmentioning
The rapalogs are the first mTOR inhibitors to show promising, yet modest, antitumor effects. To fully exploit the potential of targeting this pathway, it will be important to better understand the mechanisms of action and precise targets of the various inhibitors. Moreover, definition of biomarkers of susceptibility and identification of predictors and/or correlates to drug resistance will substantially advance this area.
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