Abstract B09: Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer

Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have so far failed. 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-κB target gene, and we have shown that NF-κB activation by KRAS requires the IKKβ kinase. Interestingly, IKKβ targeting only minimally affects KRAS-mutant cell growth in vitro, nonetheless it significantly reduces KRAS-induced lung tumor growth in situ. Therefore, we hypothesized that IKKβ inhibition would reduce KRAS-induced lung tumor growth by impairing angiogenesis. To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines A549 and H358, both by RNAi and by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor. Both approaches reduced expression and secretion of IL-8 and VEGF, another NF-κB-regulated proangiogenic growth factor. Moreover, conditioned media from IKKβ-targeted lung cells reduced endothelial cell migration and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and angiogenesis in vivo. Finally, we determined that IKKβ inhibition can affect endothelial cell function independently of cancer cells as well, as CmpdA treatment directly reduced endothelial cell migration and reduced pathologic retinal angiogenesis in a mouse model of neonatal retinopathy. Taken together, these results suggest that IKKβ inhibition therapy may be an important general antiangiogenic therapy and may reduce KRAS-induced lung tumor angiogenesis, thereby providing a clinical therapeutic benefit for lung cancer patients harboring KRAS mutations. Citation Format: Tatiana C. Carneiro-Lobo, Edmilson Ozorio dos Santos, Luiza Coimbra Scalabrini, Laura B. Cardeal, Albert S. Baldwin, Ricardo Jose Giordano, Daniela S. Basseres. Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B09.