Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Rapalogs show preclinical promise for multiple myeloma (MM) but have limited clinical success.
• Rapalogs inhibit the mammalian target of rapamycin kinase, primarily affecting the target of rapamycin complex 1 (TORC1).
• The role of the target of rapamycin complex 2 (TORC2) in MM remains less understood.

Purpose of the Study:

• To investigate the efficacy of pp242, a novel agent targeting both TORC1 and TORC2, in multiple myeloma (MM).
• To determine if TORC2 is a viable therapeutic target in MM.
• To explore potential mechanisms of TORC2 activation in MM and synergistic effects with other treatments.

Main Methods:

• Treatment of MM cells with pp242 and rapamycin, assessing phosphorylation of TORC1 and TORC2 substrates.
• Evaluation of cytoreduction and apoptosis induction in MM cells.
• In vitro studies with primary MM cells and in vivo studies using mouse models.
• Knockdown of rictor, a TORC2 component.
• Immunostaining of primary MM specimens for phosphorylated AKT.
• Combination therapy with pp242 and bortezomib.

Main Results:

• Pp242 inhibited TORC1 substrates similarly to rapamycin but also effectively inhibited TORC2 substrate phosphorylation (AKT serine 473), unlike rapamycin.
• Pp242 demonstrated superior cytoreduction and apoptosis induction in MM cells compared to rapamycin.
• Pp242 showed efficacy against primary MM cells in vitro and in a mouse model.
• Rictor knockdown was detrimental to MM cells, supporting TORC2 as a critical target.
• TORC2 activation was common in primary MM specimens.
• Combining pp242 with bortezomib resulted in synergistic anti-MM effects.

Conclusions:

• The target of rapamycin complex 2 (TORC2) is a critical therapeutic target in multiple myeloma (MM).
• Pp242, by inhibiting both TORC1 and TORC2, offers a more effective therapeutic strategy than rapamycin for MM.
• Targeting TORC2, potentially in combination with other agents like bortezomib, holds significant promise for MM treatment.