Abstract 1379: IKKβ is a potential anti-angiogenic therapeutic target in KRAS-induced lung cancer
Authors: Lobo Tatiana C. , Magalhães Leila , Cardeal Laura , Giordano Ricardo , Baldwin Albert , Bassères Daniela 
Published: August 2015

Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have been ineffective to date. An alternative route for blocking RAS-driven oncogenic pathways is to target downstream effectors of RAS involved in promoting the oncogenic phenotype. One of the critical characteristics required for tumors to grow and progress is the ability of tumor cells to drive angiogenesis. Interestingly, oncogenic RAS promotes angiogenesis by upregulating the proangiogenic IL-8 cytokine, an NF-kB target gene; and recent studies have shown that oncogenic RAS also activates the NF-κB transcription factor pathway and that KRAS-induced lung tumorigenesis is suppressed by expression of a degradation-resistant form of the IκBα inhibitor or by genetic or pharmacological inhibition of IKKβ or deletion of the RELA/p65 subunit of NF-κB. Therefore, we hypothesized that IKKβ inhibition would reduce KRAS-induced angiogenesis and tumor progression. To test this hypothesis, we used genetic and pharmacological approaches to inhibit IKKβ in K-Ras mutant lung cancer cell lines. Treatment of KRAS-positive A549 e H358 lung cancer cells with the highly specific IKKβ inhibitor Compound A (CmpdA) or siRNA-mediated knockdown of IKKβ in these cells reduced expression and secretion of the proangiogenic IL-8 cytokine. We found that IKKβ targeting also reduced expression and secretion of VEGF, a growth factor involved in promoting angiogenesis, which is also regulated by NF-κB. Moreover, conditioned media from A549 and H358 cells with siRNA-mediated IKKβ knockdown reduced endothelial cell (HUVECS) migration. In order to ascertain whether IKKβ inhibition can directly affect endothelial cell function, we treated HUVECs with CmpdA, which also resulted in reduced HUVEC migration. To evaluate how IKKβ affects endothelial cell function in vivo, we used a mouse model of neonatal retinopathy, where pathological retinal angiogenesis is induced by transient exposure of neonatal mice to hyperoxic conditions. Angiogenesis was significantly reduced in this model when neonatal mice were treated with 3 doses of 10 mg/Kg CmpdA. Finally, IKKβ knockdown in A549 cells also reduced expression of MMP-2 and MMP9 metalloproteases and reduced A549 cell invasion. Taken together, these results suggest that IKKβ inhibition therapy may reduce tumor angiogenesis, as well as invasive properties of KRAS-induced lung tumors, thereby having the potential to result in a sustained therapeutic effect, particularly if combined with other therapeutic approaches.

Citation Format: Tatiana C. Lobo, Leila Magalhães, Laura Cardeal, Ricardo Giordano, Albert Baldwin, Daniela Bassères. IKKβ is a potential anti-angiogenic therapeutic target in KRAS-induced lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1379. doi:10.1158/1538-7445.AM2015-1379