Defining the role of TORC1/2 in multiple myeloma
Patricia Maiso1, Yi Liu, Brittany Morgan
1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment to regulate multiple cellular processes. Rapamycin and its analogs have not shown significant activity in multiple myeloma (MM), likely because of the lack of inhibition of TORC2. In the present study, we investigated the baseline activity of the PI3K/Akt/mTOR pathway TORC1/2 in MM cell lines with different genetic abnormalities. TORC1/2 knock-down led to significant inhibition of the proliferation of MM cells, even in the presence of BM stromal cells. We also tested INK128, a dual TORC1/2 inhibitor, as a new therapeutic agent against these MM cell lines. We showed that dual TORC1/2 inhibition is much more active than TORC1 inhibition alone (rapamycin), even in the presence of cytokines or stromal cells. In vitro and in vivo studies showed that p-4EBP1 and p-Akt inhibition could be predictive markers of TORC2 inhibition in MM cell lines. Dual TORC1/2 inhibition showed better inhibition of adhesion to BM microenvironmental cells and inhibition of homing in vivo. These studies form the basis for further clinical testing of TORC1/2 inhibitors in MM.
Insights
Dual TORC1/2 inhibitors show significant promise for treating multiple myeloma (MM) by effectively inhibiting cancer cell proliferation and adhesion. This approach offers improved efficacy over single TORC1 inhibition, paving the way for new MM therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) pathway dysregulation is implicated in multiple myeloma (MM) pathogenesis.
- Existing therapies targeting mTOR, like rapamycin, show limited efficacy in MM due to incomplete pathway inhibition.
Purpose of the Study:
- To investigate the activity of the PI3K/Akt/mTOR pathway, including TORC1 and TORC2, in MM cell lines.
- To evaluate the therapeutic potential of dual TORC1/2 inhibition using INK128 in MM.
Main Methods:
- Assessed baseline PI3K/Akt/mTOR pathway activity in MM cell lines with genetic variations.
- Utilized TORC1/2 knock-down and INK128 (a dual TORC1/2 inhibitor) for in vitro and in vivo studies.
- Examined phosphorylation of 4E-BP1 and Akt as potential biomarkers for TORC2 inhibition.
Main Results:
- TORC1/2 knock-down significantly inhibited MM cell proliferation, even with bone marrow stromal cells present.
- Dual TORC1/2 inhibition with INK128 demonstrated superior activity compared to TORC1 inhibition alone (rapamycin).
- Dual TORC1/2 inhibition effectively reduced MM cell adhesion to bone marrow microenvironmental cells and inhibited homing in vivo.
Conclusions:
- Dual TORC1/2 inhibition is a potent strategy against multiple myeloma.
- Phosphorylated 4E-BP1 and Akt may serve as predictive markers for TORC2 inhibition in MM.
- These findings support the clinical investigation of TORC1/2 inhibitors for MM treatment.
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