KLF5 Inhibition Reduces Tumor Growth and Sensitizes to Chemotherapy-Induced Cell Death in Experimental Models of CCA

Researchers evaluated KLF5 expression and its inhibition in cholangiocarcinoma using clustered regularly interspaced short palindromic repeats technology.

Cholangiocarcinoma (CCA) makes up a group of heterogeneous cancers associated with poor prognosis. Krüppel-like factors (KLF) are a family of transcription factors that play a variety of roles, including organogenesis, differentiation, and cellular homeostasis. At the 2023 ESMO Congress, Ana Landa-Magdalena presented the role of KLF5 in CCA development and evaluated the therapeutic potential of its inhibition in experimental models of CCA.

KLF5 expression was measured in human CCA tissues from 5 different cohorts (Copenhagen [n=210], TCGA [n=36], Job [n=78], TIGER-LC [n=90], and San Sebastian [n=12]) and cell lines. KLF5^-/- (homozygous mutations) CCA cells were created using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9. The functional effects of genetic silencing of KLF5 using CRISPR technology or chemical inhibition with ML264 were evaluated in vitro and in vivo.

Compared with surrounding healthy liver tissue, KLF5 expression was upregulated in human CCA tissues from Copenhagen, TCGA, Job, TIGER-LC, and San Sebastian patient cohorts. High KLF5 levels were associated with lymph-node invasion and reduced overall survival. Compared with healthy human cholangiocytes, KLF5 protein and mRNA levels were overexpressed in human CCA cells in vitro. When compared with control cells, KLF5^-/- CCA cells displayed decreased cell proliferation, migration, invasion, and colony formation while promoting cell cycle arrest and apoptosis in vitro. KLF5^-/- CCA cells did not develop any tumors after subcutaneous or orthotopic injection in a xenograft animal model of CCA. Likewise, chemical inhibition of KLF5 with ML264 hampered CCA cells’ proliferation and migration in vitro and blocked tumor growth in vivo. Finally, both genetic and chemical inhibition of KLF5 sensitized CCA cells to chemotherapy-induced apoptosis in vitro, and the combination of gemcitabine/cisplatin and ML264 completely halted CCA tumor growth in mice. In addition, KLF5^-/- CCA cells displayed altered levels of several proteins related to chemoresistance when compared with control cells and were shown to significantly correlate with KLF5 expression in human CCA tissues.

These findings suggest that increased KLF5 expression contributes to cancer progression by its promotion of cell survival and proliferation and chemoresistance in CCA. KLF5 inhibition with ML264 may be a potential therapeutic target for CCA.

Source:

Landa-Magdalena A, Rodrigues PM, Erice O, et al. Inhibition of KLF5 reduces tumor growth and sensitizes to chemotherapy-induced cell death in experimental models of cholangiocarcinoma. Presented at: ESMO Congress 2023, October 20-24, 2023; Madrid, Spain.