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Page 10 of 20 Ho et al. J Cancer Metastasis Treat 2019;5:70 I http://dx.doi.org/10.20517/2394-4722.2019.25

mTORC2 [132,133] . In line with this, it has been reported that when used in combination with bortezomib,
[65]
the autophagy inhibitors 3-methyladenine or chloroquine can also have an antagonistic effect . One
potential explanation could be that bortezomib induces apoptosis partially through autophagic cell death.
Consistent with a role for autophagic cell death in MM cells treated with bortezomib, a novel SCF (Skp2)
inhibitor CpdA stabilizes p27 to induce caspase-independent autophagic cell death in MM cells resistant to
[134]
bortezomib; and also synergized with bortezomib . Another compound, betulinic acid (BetA), activates
protein phosphatase 2A (PP2A) to trigger DAPK-dependent autophagic cell death in MM cells with high
[135]
BCL-2 expression .

Autophagy inhibitors have also shown potency in bortezomib and carfilzomib-resistant MM cells . The
[136]
non-selective HDAC inhibitor SBHA upregulates the BH3-only protein BIM, which in turn sequesters
BECLIN-1 to inhibit cytoprotective autophagy, thereby overcoming acquired bortezomib resistance .
[136]
Chloroquine potentiated carfilzomib cytotoxicity and was able to overcome carfilzomib resistance
in vitro [137] . Lastly, pharmacologic inhibition of thioredoxin with PX12 upregulates mitophagy to re-
[73]
sensitize bortezomib-resistant cells to bortezomib . Combination treatment of MM cells with PX12
and bortezomib led to synergistic toxicity and inhibition of ERK1/2 and mTOR signaling, suggesting the
[73]
involvement of ERK1/2 and mTOR in mitophagy suppression .
PI3K-AKT-mTOR inhibitors
While activating mutations in PI3K and AKT have not been reported in MM, the PI3K-AKT-mTOR
pathway is commonly activated in MM through juxtacrine and paracrine signaling within the MM tumor
microenvironment [138,139] . Interactions between MM and the stromal and endothelial compartments result
in the secretion of IL-6, VEGF, and IGF-1, which in turn activate pro-survival and proliferative pathways
such as PI3K-AKT-mTOR, JAK/STAT3, NFkB, and MEK/ERK . In line with this, efforts to inhibit PI3K-
[139]
AKT-mTOR signaling have led to the study of mTORC1 inhibitors (e.g., rapamycin) in MM. However,
results from preclinical studies were disappointing as rapamycin and the other rapalogs demonstrated
[140]
a cytostatic, but not cytotoxic, response in MM . This lack of potency could be due, in part, to the
activation of cytoprotective autophagy. Nonetheless, mTORC1 inhibitors have shown synergistic activity in
other cancers when used in combination with clinically approved anti-MM agents such as dexamethasone,
lenalidomide, and panobinostat, and pre-clinical agents such as sorafenib (tyrosine kinase inhibitor),
17-AAG (HSP90 inhibitor), NVP-AEW541 (IGF1R inhibitor), and MK2206 (AKT inhibitor) [141-148] .

Upstream of mTOR, AKT inhibitors have also been studied in MM. In preclinical studies, perifosine,
an AKT inhibitor, was cytotoxic to MM cells as a single-agent and also synergized with bortezomib,
[149]
dexamethasone, doxorubicin, melphalan, and U0126 (MEK1/2 inhibitor) . Another AKT inhibitor TAS-117
[150]
enhanced ER stress and MM apoptosis when added to bortezomib or carfilzomib . These studies once
again highlight the duality of autophagy in MM, suggesting that excessive induction of autophagy, rather
than protecting cells from excessive ER stress, pushes cells towards autophagic cell death.

The next class of PI3K-AKT-mTOR pathway inhibitors are the dual PI3K-mTOR inhibitors. One such
inhibitor, BEZ235, demonstrated good preclinical single-agent activity in MM and also synergized
with bortezomib, doxorubicin, and melphalan [151,152] . Another study reported a pro-survival function of
autophagy in MM cells treated with PI-103, a competitive dual PI3K and mTOR inhibitor, which inhibits
the proteasome, induces UPR, and upregulates autophagy . Importantly, Bafilomycin-A, an autophagy
[153]
[153]
inhibitor, enhanced apoptosis in cells treated with PI-103 .
Heat-shock protein inhibitors
Heat shock proteins are molecular chaperones that play indispensable roles in protein folding/unfolding,
[154]
multiprotein complex assembly, and protein sorting . As a function of protein sorting, HSP70 and HSP90