IKKb kinase promotes stemness, migration, and invasion in KRAS-driven lung adenocarcinoma cells

KRAS oncogenic mutations are widespread in lung cancer and, because direct targeting of
KRAS has proven to be challenging, KRAS-driven cancers lack eective therapies. One alternative
strategy for developing KRAS targeted therapies is to identify downstream targets involved
in promoting important malignant features, such as the acquisition of a cancer stem-like and
metastatic phenotype. Based on previous studies showing that KRAS activates nuclear factor
kappa-B (NF-B) through inhibitor of nuclear factor kappa-B kinase (IKK) to promote lung
tumourigenesis, we hypothesized that inhibition of IKK would reduce stemness, migration
and invasion of KRAS-mutant human lung cancer cells. We show that KRAS-driven lung
tumoursphere-derived cells exhibit stemness features and increased IKK kinase activity. IKK
targeting by dierent approaches reduces the expression of stemness-associated genes, tumoursphere
formation, and self-renewal, and preferentially impairs the proliferation of KRAS-driven lung
tumoursphere-derived cells. Moreover, we show that IKK targeting reduces tumour cell migration
and invasion, potentially by regulating both expression and activity of matrix metalloproteinase 2
(MMP2). In conclusion, our results indicate that IKK is an important mediator of KRAS-induced
stemness and invasive features in lung cancer, and, therefore, might constitute a promising strategy to
lower recurrence rates, reduce metastatic dissemination, and improve survival of lung cancer patients
with KRAS-driven disease.