BACKGROUND: Resistance to the targeting of protein degradation by the standard-of-care proteasome inhibitors (PI) therapy in multiple myeloma (MM) remains a challenge. Recent studies implicate altered ribosome synthesis and mRNA translation activity in driving MM disease progression and resistance to therapy. Indeed, selective inhibition of RNA polymerase I transcription by CX-5461, which inhibits ribosome synthesis, has shown efficacy in pre-clinical models of MM and therapeutic benefit in 3/6 patients with relapsed/refractory MM (RRMM) in a phase I clinical trial. We thus propose CX-5461 in combination strategies will produce durable responses in RRMM.
AIM: To define the molecular response to CX-5461 in MM and examine the efficacy of CX-5461 as a single agent and in combination with other agents having proven clinical or promising preclinical efficacy in MM.
METHODS: We measured the effects of CX-5461 in human myeloma cell lines (HMCLs) and 5T33 and 5TGM1 murine MM cells in vitro and in vivo. A high-throughput screen of HMCLs in response to CX-5461 in combination with different therapeutic agents was conducted. Agents producing synergistic interactions with CX-5461 were identified and tested in murine Vk*MYC and 5T33-KaLwRij MM models.
RESULTS: CX-5461 has potent antimyeloma activity in PI-sensitive and PI-resistant MM models in vitro and in vivo, though the addition of PI does not further enhance the therapeutic benefit of CX-5461 in vivo. Interestingly, CX-5461 shows synergistic interactions with the histone deacetylase inhibitor (HDCAi) panobinostat in vitro and in vivo and the combination targets ribosome biogenesis and function leading to enhanced inhibition of protein synthesis via distinct mechanisms.
FUTURE PLANS: Our findings provide strong evidence to facilitate the clinical development of targeting the ribosome for the treatment of RRMM. We therefore plan to further characterise mRNA translation activity and protein synthesis associated with resistance to PI and identify essential genes mediating response to CX-5461 using a genome-wide CRISPR/Cas9 synthetic lethal screen. The results will provide new insights into the molecular mechanisms underlying disruption in protein homeostasis driving MM disease progression and therapeutic response, facilitate the clinical development of ribosome-targeting therapy in effective combination strategies for the treatment of RRMM.