A RALGEF inhibitor suppresses lung cancer stem cell development and tumorigenesis.

Genetic studies have implicated RAL proteins as key components of RAS mediated transformation and metastasis. They can modulate drug resistance, the cancer stem cell population and the exocyst transport system. RAL proteins are activated by RALGEFs (Guanine Nucleotide Exchange Factors). A conserved family of four RALGEFs serve as direct effectors of the RAS oncoprotein, connecting RAS to the regulation of RAL proteins. We have previously reported the development of a first-in-class small molecule inhibitor of RALGEFs that acts by binding to the RAS association domain of RALGEFs, blocking their interaction with RAS and suppressing the activation of RAL. Here we show the agent is active in KRAS driven non-small cell lung cancer (NSCLC) models, both in vitro and in vivo using cell line and transgenic models of lung cancer. Moreover, we show that it acts to suppress the anti-porter activity of the RAL effector protein RALBP1, sensitizes cells to standard of care treatment and suppresses the exocyst system. Finally, we show it acts to suppress the cancer stem cell pool using biomarkers and tumor forming unit assays. Thus, we identify a potential novel therapeutic approach to NSCLC.