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Romidepsin and afatinib combination treatment induce synergistic anti-lymphoma effect in CTCL

ABSTRACT: Cutaneous T-cell lymphomas (CTCL) are an aggressive group of T-cell lymphomas that present in the skin and are associated with dismal prognosis. Romidepsin is a histone deacetylase (HDAC) inhibitor that is an FDA approved systemic therapeutic indicated for the treatment of CTCL in patients who have received at least one prior systemic therapy. Romidepsin demonstrates promising single agent activity in patients with advanced stages of CTCL, however response is typically low and not durable. One method of overcoming resistance to romidepsin and improving response is through combination therapies. Here, we demonstrate that romidepsin in combination with the epidermal growth factor receptor (EGFR) inhibitor afatinib and afatinib dimaleate produce strongly synergistic anti-tumor effects in CTCL cell lines and an in vivo model of CTCL. Gene expression and western blot analysis further identifies the decreased activation of the JAK-STAT signalling pathway as a key driver of synergy in this combination. These results suggest a potential indication for FDA-approved EGFR inhibitors previously unrecognized in CTCLs as a combination therapeutic with HDAC inhibitors that can be rapidly adopted in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237167 | GEO | 2024/07/12

REPOSITORIES: GEO

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Project description:EGFR tyrosine kinase inhibitors (TKIs) have demonstrated tremendous clinical benefits in non-small cell lung cancer (NSCLC) patients. However, resistance emerges rapidly due to a variety of mechanisms including a secondary mutation of T790M in EGFR that abrogates the binding of the drugs. It has been postulated that EGFR TKIs, such as afatinib (BIBW2992), with activity against the T790M mutant EGFR kinase might overcome the drug resistance problem or, when used as the first-line treatment, delay or suppress the emergence of resistance in EGFR. In this study, we generated BIBW2992-resistant cells, HCC827-BR1 and HCC827-BR2, from the parental HCC827 cells. In HCC827-BR cells, EGFR, MET, and Erb2 were down-regulated and no secondary mutation was found to be present in the coding region of EGFR. Gene set enrichment analysis (GSEA) revealed an obvious signature of epithelial to mesenchymal transition (EMT) in the drug resistant cells. Subsequently, the HCC827-BR cells were shown to be more invasive. Most importantly, we strived to seek if alternative medicine might be applied alone or in combination to treat the BIBW2992-resistant cells or to, under BIBW2992 treatment, diminish the emergence of resistant cells. Compared to the parental cells, the HCC827-BR cells were more sensitive to dasatinib, an FDA-approved kinase inhibitor. Furthermore, as revealed in the clonogenicity assay, the reduction of tumor-colony-forming cells after exposure to BIBW2992 was substantially potentiated by low concentration of dasatinib. Thus, prospective clinical investigations may be needed to evaluate if dasatinib can be beneficial to patients receiving second-generation EGFR TKIs for the treatment of NSCLC. Over a period of 3-4 months, BIBW2992-resistant cells were isolated in cell culture by maintenance of HCC827 cells in the presence of escalating concentrations of BIBW2992 up to 2 Î¼M. Two cell lines, HCC827-BR1 and HCC827-BR2, were established based on individual clones. Total RNA of these HCC827, HCC827-BR1 and HCC827-BR2, were extracted for gene expression microarray analysis using Illumina HumanHT12 v3 BeadChip.

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Romidepsin and afatinib combination treatment induce synergistic anti-lymphoma effect in CTCL

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