Abstract
KRAS oncogenic mutations are widespread in lung cancer and, because direct targeting of KRAS has proven to be challenging, KRAS-driven cancers lack effective 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-κB) through inhibitor of nuclear factor kappa-B kinase β (IKKβ) to promote lung tumourigenesis, we hypothesized that inhibition of IKKβ 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 IKKβ kinase activity. IKKβ targeting by different 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 IKKβ 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 IKKβ 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.
Highlights
Lung cancer is the main cause of cancer-related deaths in the world, and despite the increasing advances in the development of new, targeted therapies, the 5-year survival rates remain lower than 20%
Using an established tumoursphere formation assay [15,26] to enrich for lung tumour-initiating cells (TICs), we show that inhibitor of nuclear factor kappa-B kinase β (IKKβ) is critical to sustain stemness-associated features in KRAS-driven lung cancer cells
We found that matrix metalloproteinases 2 (MMP2) activity is reduced by IKKβ or KRAS targeting in both A549 and H358 cells (Figure 6B), whereas IKKβ or KRAS targeting did not affect MMP9 activity (Figure 6B)
Summary
Lung cancer is the main cause of cancer-related deaths in the world, and despite the increasing advances in the development of new, targeted therapies, the 5-year survival rates remain lower than 20%. NF-κB activation by oncogenic KRAS in the lung involves the canonical pathway [21] and requires IKKβ [22] Based on this evidence we hypothesized that IKKβ would promote KRAS-driven lung cancer stemness and invasion. In support of this hypothesis, genetic or systemic IKKβ inhibition reduces KRAS-induced lung tumour growth by reducing cell proliferation [22,23], and reduces KRAS-induced angiogenesis [24], a cancer hallmark that is associated with poor prognosis and contributes to the process of metastasis [25]. Our data suggest that IKKβ kinase inhibition therapy may clinically benefit KRAS-driven lung cancer patients by depleting the pool of stem-like TICs, thereby decreasing the risk of tumour recurrence and metastasis
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