RNA sequencing analysis of TNBC PDX treated with MLK3 and pan MLK's inhibitor
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ABSTRACT: Mixed Lineage Kinase 3 (MLK3) is a viable emerging target for neoplastic diseases; however, it is uncertain whether its activators or inhibitors can act as anti-neoplastic agents. Previously, we reported that the kinase activity of MLK3 was significantly higher in triple-negative breast cancer (TNBC) than hormone receptor-positive human breast tumors where estrogen inhibits MLK3 kinase activity and provides a survival advantage to ER+ breast cancer cells. Here, we identified that in TNBC, the higher MLK3 kinase activity paradoxically promotes cell survival via activating the downstream PAK1-NF-kB axis. The MLKs/MLK3 inhibitors, CEP-1347, and URMC-099 induced cell death in TNBC but not in hormone receptor-positive breast cancer cells. The MLKs/MLK3 inhibitors reduced TNBC cell line and patient-derived xenografts’ tumor burden. The MLKs/MLK3 inhibitors also decreased MLK3, PAK1, and NF-kB protein expression and activation, prompting cell death in breast PDXs. The RNA-seq analyses indicated several genes downregulated upon MLKs/MLK3 inhibition in tumors. Significantly NGF/TrkA MAPK pathway was enriched in tumors undergoing tumor reduction by CEP-1347 and URMC-099. The tumors or cell lines that did respond to MLKs/MLK3 inhibitors had higher TrkA expression, and TrkA overexpression in the presence of MLK3 sensitized the TNBC cell line that initially did not respond to MLKs/MLK3 inhibitors. These results suggest that the functions of MLK3 in cancer cells are dependent on downstream targets/signaling, and rationalized decision needs to be made before using its inhibitor in different breast cancer subtypes. Our data also highlight that MLK3 inhibitor warrants further investigation for treating TNBC.
ORGANISM(S): Homo sapiens
PROVIDER: GSE188947 | GEO | 2023/03/01
REPOSITORIES: GEO
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