Using global proteomics to investigate the effect of IQDMA treatment on Leukemic forms of cutaneous T-cell lymphomas (L-CTCL) cells

ABSTRACT: Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Skin

DISEASE(S): Lymphoma

SUBMITTER: Abootaleb Sedighi  

LAB HEAD: Patrick Gunning

PROVIDER: PXD035699 | Pride | 2022-10-06

REPOSITORIES: Pride