Autophagy: A Potential Therapeutic Target to Tackle Drug Resistance in Multiple Myeloma

Abstract

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. In the past few years, the survival of MM patients has increased due to the emergence of novel drugs and combination therapies. Nevertheless, one of the significant obstacles in treating most MM patients is drug resistance, especially for individuals who have experienced relapses or developed resistance to such cutting-edge treatments. One of the critical processes in developing drug resistance in MM is autophagic activity, an intracellular self-digestive process. Several possible strategies of autophagy involvement in the induction of MM-drug resistance have been demonstrated thus far. In multiple myeloma, it has been shown that High mobility group box protein 1 (HMGB1)-dependent autophagy can contribute to drug resistance. Moreover, activation of autophagy via proteasome suppression induces drug resistance. Additionally, the effectiveness of clarithromycin as a supplemental drug in treating MM has been reported recently, in which autophagy blockage is proposed as one of the potential action mechanisms of CAM. Thus, a promising therapeutic approach that targets autophagy to trigger the death of MM cells and improve drug susceptibility could be considered. In this review, autophagy has been addressed as a survival strategy crucial for drug resistance in MM.

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

“…In MM, it high mobility group box protein 1 (HMGB1)-dependent autophagy can contribute to drug resistance. 45 Autophagy blockade disrupts myeloma cell recovery through proteasome inhibition and enhances apoptosis. 46 Strikingly, our study demonstrated that CRIP1 overexpression induced the drug-resistance to PIs depending not only on the increase in proteasome activity, but also on the maturation of autophagy.…”

An inflammatory response-related gene signature can predict the prognosis and impact the immune infiltration of multiple myeloma

“…Once tumors are formed, tumor cells use autophagy to ensure their survival under nutrient-deficient and hypoxic conditions [ 34 ]. So far autophagy has been also demonstrated to be involved in the induction of MM-drug resistance [ 35 ]. Beside, we also found PI3K-Akt signaling pathway was activated and enriched in up-regulated genes subgroup, which is a conventional inflammatory signaling pathways involved in cancer development [ 36 ].…”

Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity

“…For instance, alterations in drug-binding sites might reduce the activity of PIs to inhibit proteolysis. Activation of the autophagy-lysosomal pathway to compensate for proteasome inhibition is another mechanism for resistance ( 5 , 6 ). Upregulation of survivin, an apoptosis inhibitor, has been shown to play a role in decreased response to proteasome inhibition mainly by bortezomib (BTZ) ( 7 ).…”