Targeting the PI3K/AKT/mTOR Pathway in Non-Hodgkin’s Lymphoma: Results, Biology, and Development Strategies

Abstract

Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin's lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50%, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.

mTOR Inhibitors in Cancer Treatment

“…Mabuchi and colleagues assessed the expression of phospho (p)-mTOR using tissue microarrays of 98 primary ovarian cancers. The authors highlighted that mTOR was more frequently activated in clear-cell carcinomas than in serous adenocarcinomas (86.6 vs 50%) [4]. In this study, growth inhibition of mTOR by RAD001 was noted in both cisplatin-sensitive and -resistant cell lines; however, the cisplatin-resistant cell lines showed greater sensitivity to RAD001 than did the sensitive cell lines.…”

“…The two other pathways include the PKC family and the RAS/ MAPK cascades. Various receptor tyrosine kinases that may be expressed by cancers cells, such as VEGFR-1 [2], PDGFR-a [3], EGFR [4] or c-MET [5], utilize the PI3K/Akt/mTOR signaling pathway to shape the phenotype and function of malignant cells.…”

“…Several comprehensive reviews [1][2][3][4] on this topic state that altered gene expression may be related to:…”

Reversal of multidrug resistance by cisplatin-loaded magnetic Fe3O4 nanoparticles in A549/DDP lung cancer cells in vitro and in vivo

“…13 Patient-derived tumor xenografts may also play a key role in the search for more reliable multidrug resistance markers. There is accumulating evidence that several chemotherapeutic agents involved in the treatment of cancer interfere with the phosphatidylinositol 3-kinase/Akt pathway, 14 in which abnormalities of the signal transduction pathway are important in tumorigenesis and tumor progression. Akt is a cytosolic intracellular signal transduction protein that may be a prognostic factor by being closely associated with the development and progression of NSCLC.…”

Synergistic effect of a combination of nanoparticulate Fe3O4 and gambogic acid on phosphatidylinositol 3-kinase/Akt/Bad pathway of LOVO cells

“…The phosphatidylinositol 3-kinase (PI3K/ Akt) pathway acts as a critical regulator of cell survival by stimulating cell proliferation and inhibiting apoptosis, and abnormal signal transduction pathways are important in tumorigenesis and tumor progression. 17 Bad, a member of the Bcl-2 family, is one of several substrates for Akt. 18 Phosphorylation of Bad by Akt suppresses its auxo-apoptotic functions, accounting in part for the potent survival function of Akt.…”