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Updated: Jun 28, 2025
Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube SWCNT-delivered MALAT1 Antisense Oligos
Published on: December 13, 2018
Targeting the ribosome to treat multiple myeloma
Kylee H Maclachlan1,2,3, Kezia Gitareja4,5, Jian Kang4,5
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Abstract:
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 (PIs) has revolutionized the treatment of MM. However, resistance to PIs 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 anti-myeloma 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. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 in vivo. 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.
Insights
CX-5461 effectively targets multiple myeloma (MM) cells by inhibiting ribosome biogenesis, showing promise against proteasome inhibitor-resistant cancer. It synergizes with other drugs, offering new hope for relapsed and refractory MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Multiple myeloma (MM) cells have high protein synthesis rates, making them vulnerable to proteasome inhibitors (PIs).
- Resistance to PIs is a significant clinical challenge in MM treatment.
- CX-5461, an RNA polymerase I inhibitor, has shown preliminary anti-tumor activity in MM patients.
Purpose of the Study:
- To evaluate the anti-myeloma activity of CX-5461 in proteasome inhibitor-resistant models.
- To investigate the mechanisms of action of CX-5461 in multiple myeloma.
- To explore synergistic combinations of CX-5461 with other anti-myeloma agents.
Main Methods:
- In vitro and in vivo preclinical models of PI-resistant MM (Vk*MYC and 5T33-KaLwRij mouse models).
- Assessment of CX-5461's effects on ribosome biogenesis, DNA damage, and cell-cycle arrest.
- Combination studies with proteasome inhibitors and panobinostat.
Main Results:
- CX-5461 demonstrated potent anti-myeloma activity in PI-resistant MM models.
- CX-5461 inhibits ribosome biogenesis, induces DNA damage, and causes cell death.
- CX-5461 showed synergistic effects with panobinostat but not with PIs in vivo.
Conclusions:
- CX-5461 exhibits significant anti-myeloma activity, even in PI-resistant settings.
- Targeting ribosome biogenesis is a viable strategy for treating relapsed and refractory MM.
- CX-5461 in combination with panobinostat warrants further clinical investigation for MM treatment.
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