However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence.
We tested the effect of pan-class I PI3K inhibition by siRNA silencing or pharmacologic inhibition with buparlisib on MM cell survival, apoptosis and cell cycle in vitro and tumor growth and mobilization of MM cells in vivo.
Induction of ER stress and apoptosis by the p97 inhibitor CB-5083 was strongly enhanced in combination with the PI3Kα inhibitor BYL-719 or the HDAC inhibitor panobinostat suggesting potential therapeutic strategies to circumvent IXA resistance in MM.
Concomitant pan-Raf/PI3K inhibition was also effective in carfilzomib- and lenalidomide-resistant MM models underscoring that this attractive therapeutic anti-MM strategy is suitable for immediate clinical translation.
Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K (phosphoinositide 3-kinase)/Akt signaling, and increased DNMT3A (DNA methyltransferase 3A) expression, resulting in hypermethylation of RUNX2, osterix, and IRF8 This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients.
Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions.
We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells.
The PI3K/Akt/mTOR signal transduction pathway plays a central role in multiple myeloma (MM) disease progression and development of therapeutic resistance. mTORC1 inhibitors have shown limited efficacy in the clinic, largely attributed to the reactivation of Akt due to rapamycin induced mTORC2 activity.
The PI3K/Akt/mTOR pathway is constitutively activated in human multiple myeloma (MM) cell lines and in freshly isolated plasmocytes from patients with MM.
Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.
The results of Western blot assay showed that the PI3K/AKT/mTOR signaling pathway was activated in bone marrow specimens of patients with MM. miR-215-5p was found to negatively correlate with runt-related transcription factor 1 (RUNX1) expression in MM clinical bone marrow samples.
Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process.
Since PTEN-null myeloma lines exhibited much stronger Akt activation than PTEN-expressing cells in response to insulin-like growth factor I stimulation, we determined whether Akt could be responsible for PI3K-mediated cell survival and growth of PTEN-null myeloma lines.
Furthermore, our results demonstrated that the enforced expression of miR-145 in H929 cells profoundly decreased the levels of p-AKT and p-PI3K, which may contribute to some extent to the inhibition of MM cell proliferation and survival.
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is such a pathway that is aberrantly activated in a large proportion of MM patients through numerous mechanisms and can play a role in resistance to several existing therapies making this a central pathway in MM pathophysiology.
These results indicate that CIP2A modulates myeloma cell proliferation and apoptosis via PI3K/AKT/mTOR signaling and suggest that it can potentially serve as a drug target for the treatment of multiple myeloma.
Moreover, miR-30d carries out its antitumor role in U266 cells through the inhibition of the activation of the PI3K/Akt signaling pathway by negatively regulating MTDH, which reveals its potential for use as a therapeutic target for MM.