RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids.

Abstract

Purpose: The alternative splicing of mRNA precursors allows one gene to yield multiple proteins with distinct functions. CDC-like kinases serve as pivotal regulators of alternative splicing. Control of protein expression also occurs at the level of DNA through histone methylation and demethylation. We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents.

Methods: Well-characterized patient-derived cancer cell lines from the PDMR ( https://pdmr.cancer.gov/models/database.htm ) were used along with standard human cancer cell lines. Multi-cell type-tumor spheroids were grown from a ratio of 6:2.5:1.5 malignant cells, endothelial cells, and mesenchymal stem cells. Following three days of growth, the spheroids were exposed to the single agents or combinations at concentrations up to the clinical C_max value for each agent, if known. After seven days of exposure, cell viability was assessed using the CellTiter-Glo 3D assay and spheroid volume was assessed by bright field imaging.

Results: Several of the targeted oncology drugs exhibited additive and greater-than-additive cytotoxicity when combined with a CLK inhibitor, or the LSD1 inhibitor. These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors.

Conclusion: These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.