Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2 - implications for a combinatorial treatment

Abstract

Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-κB signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment.

Tamoxifen - DEBIO 1143 kombinasyonunun östrojen reseptörü pozitif meme kanseri hücre hatlarındaki etkisi.

“…In vitro studies conducted on the issue have shown that administration of DEBIO 1143 together with bortezomib [20] or carboplatin [4] or radiation [21] or JQ1 [22] can induce apoptosis in various cancer cell lines.…”

SMAC Mimetiği Olarak AT-406’nın Kanserdeki Rolü

“…tir. LP-1 ve ANBL-6 multiple myeloma hücre hatlarında, AT-406'nın, proteazom inhibitörlerinden birisi olan bortezomibin (PS-341) antitümoral etkisini artırdığı bulunmuştur (19). AT-406'nın proteazom inhibitörlerinin NF-κB nükleer lokalizasyonunu engelleme aracılığıyla apoptozisin indüklenmesine karşı hücrelerin hassasiyetini arttırması tedavinin daha etkili olabileceği açısından önemlidir.…”

Post-translational modification profiling – A novel tool for mapping the protein modification landscape in cancer

“…46 Other E3-targeting anticancer pharmacological agents that are in preclinical/clinical trials include small molecules targeting the p53-MDM2 interaction, inhibitors of apoptosis proteins, SKP2, and the anaphase-promoting complex/ cyclosome. [47][48][49][50][51][52][53] Thus, E3 ligase-directed therapy is indeed a promising effective approach. In this respect, the HECT domain E3 ligases are attractive potential targets for anticancer intervention as they possess a catalytic site and directly catalyze substrate ubiquitination.…”