Overcoming proteasome inhibitor resistance in the immunotherapy era

Patiño-Escobar, Bonell; Talbot, Alexis; Wiita, Arun P.

doi:10.1016/j.tips.2023.05.006

Cited by 10 publications

(8 citation statements)

References 79 publications

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“…2F). This is consistent with observed high response rates to immunotherapies in PI-refractory MM patients (42). Moreover, in PI-resistant cells, we identified reduced expression of genes involved in ribonuclease H2 complex and FACT complex which are involved in DNA repair, replication and transcription (43,44), suggesting that genomic instability maybe linked to resistance to PIs (Fig.…”

Section: Cx-5461 Has Potent Activity In Proteasome Inhibitor-resistan...supporting

confidence: 88%

Targeting the ribosome to treat multiple myeloma

Maclachlan,

Gitareja,

Kang

et al. 2023

Preprint

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The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PI) has revolutionized the treatment of MM. However, resistance to PI is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461 has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here we show that CX-5461 has potent antimyeloma activity in PI-resistant MM preclinical models in vitro and in vivo. In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell cycle arrest and apoptotic cell death. Surprisingly, the addition of PI does not enhance the therapeutic benefit of CX-5461. In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk*MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.

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Section: Cx-5461 Has Potent Activity In Proteasome Inhibitor-resistan...supporting

confidence: 88%

Targeting the ribosome to treat multiple myeloma

Maclachlan,

Gitareja,

Kang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…This is consistent with observed high response rates to immunotherapies in PI-refractory MM patients. 39 Moreover, in PI-resistant cells, we identified reduced expression of genes involved in ribonuclease H2 complex and FACT complex, which are involved in DNA repair, replication, and transcription, 40 , 41 suggesting that genomic instability may be linked to resistance to PIs ( Figures 2 H and S2 F). Accordingly, analysis of upregulated phosphorylated proteins in PI-resistant cells showed enriched signatures of DDR and regulation of DNA replication and increased ATM/CHEK2/CHEK1 kinase activities ( Figures 2 I and S2 G).…”

Section: Resultsmentioning

confidence: 92%

Targeting the ribosome to treat multiple myeloma

Maclachlan,

Gitareja,

Kang

et al. 2024

Molecular Therapy: Oncology

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“…In other words, PIs will ultimately lead to an accumulation of proteins, while drug #2 can be used to prevent the cell from overcoming the effect of the PI, e.g., by blocking lysosomal degradation [ 53 ]. PIs have recently been found to induce immunogenic cell death by activating the cGAS/STING-pathway, which could be used as a target for immunotherapy in combination with PIs to increase treatment efficacy and as a means of overcoming resistance to PIs [ 54 ]. However, future studies are warranted to evaluate this molecular mechanism in connection with PIs in more detail [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…PIs have recently been found to induce immunogenic cell death by activating the cGAS/STING-pathway, which could be used as a target for immunotherapy in combination with PIs to increase treatment efficacy and as a means of overcoming resistance to PIs [ 54 ]. However, future studies are warranted to evaluate this molecular mechanism in connection with PIs in more detail [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer

Larsson,

Pettersson,

Olsson

et al. 2024

Cell Death Discov.

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Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options due to the lack of important receptors (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) used for targeted therapy. However, high-throughput in vitro drug screening of cell lines is a powerful tool for identifying effective drugs for a disease. Here, we determine the intrinsic chemosensitivity of TNBC cell lines to proteasome inhibitors (PIs), thereby identifying potentially potent 2-drug combinations for TNBC. Eight TNBC cell lines (BT-549, CAL-148, HCC1806, HCC38, HCC70, MDA-MB-436, MDA-MB-453, and MDA-MB-468) and two controls (MCF-10A and MCF-7) were first exposed to 18 drugs (11 PIs and 7 clinically relevant chemotherapeutic agents) as monotherapy, followed by prediction of potent 2-drug combinations using the IDACombo pipeline. The synergistic effects of the 2-drug combinations were evaluated with SynergyFinder in four TNBC cell lines (CAL-148, HCC1806, HCC38, and MDA-MB-468) and three controls (BT-474, MCF-7, and T47D) in vitro, followed by further evaluation of tumor regression in zebrafish tumor models established using HCC1806 and MCF-7 cells. Monotherapy identified nine effective drugs (bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. PIs (e.g., bortezomib, delanzomib, and epoxomicin) were highly potent drugs in TNBC cells, of which bortezomib and delanzomib inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 µM. Moreover, several potent 2-drug combinations (e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identified. Although HCC1806- and MCF-7-derived xenografts treated with bortezomib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells frequently metastasized to the trunk region. Taken together, we show that PIs used in combination with platinum agents or topoisomerase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that PIs are therefore promising compounds to use as combination therapy for TNBC.

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Overcoming proteasome inhibitor resistance in the immunotherapy era

Cited by 10 publications

References 79 publications

Targeting the ribosome to treat multiple myeloma

Targeting the ribosome to treat multiple myeloma

Targeting the ribosome to treat multiple myeloma

Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer

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