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Ponatinib sensitizes myeloma cells to MEK inhibition in the high-risk VQ model. | LitMetric

AI Article Synopsis

  • Multiple myeloma (MM) is a type of cancer that affects plasma cells, and it's often resistant to common treatments, especially in advanced stages with genetic mutations in the RAS pathway.
  • Researchers developed a mouse model called VQ MM to study this advanced form and screened 147 FDA-approved anti-cancer drugs, finding that the combination of trametinib (Tra) and ponatinib (Pon) was particularly effective, prolonging survival in mice.
  • However, ponatinib negatively impacted the function of CD8 T cells, which are important for immune response, suggesting that while it enhances treatment effects, it may also reduce immune response, highlighting the need for balanced therapy approaches.

Article Abstract

Multiple myeloma (MM) is a malignant plasma cell cancer. Mutations in RAS pathway genes are prevalent in advanced and proteasome inhibitor (PI) refractory MM. As such, we recently developed a VQ MM mouse model recapitulating human advanced/high-risk MM. Using VQ MM cell lines we conducted a repurposing screen of 147 FDA-approved anti-cancer drugs with or without trametinib (Tra), a MEK inhibitor. Consistent with its high-risk molecular feature, VQ MM displayed reduced responses to PIs and de novo resistance to the BCL2 inhibitor, venetoclax. Ponatinib (Pon) is the only tyrosine kinase inhibitor that showed moderate MM killing activity as a single agent and strong synergism with Tra in vitro. Combined Tra and Pon treatment significantly prolonged the survival of VQ MM mice regardless of treatment schemes. However, this survival benefit was moderate compared to that of Tra alone. Further testing of Tra and Pon on cytotoxic CD8 T cells showed that Pon, but not Tra, blocked T cell function in vitro, suggesting that the negative impact of Pon on T cells may partially counteract its MM-killing synergism with Tra in vivo. Our study provides strong rational to comprehensively evaluate agents on both MM cells and anti-MM immune cells during therapy development.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226136PMC
http://dx.doi.org/10.1038/s41598-022-14114-zDOI Listing

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