Lipid Nanoparticle Delivery of iMDK Induces ATF3-Mediated Apoptosis in Sotorasib-Resistant KRAS Mutant Lung Cancer

The small molecule iMDK induces apoptosis in H441 papillary lung adenocarcinoma cells that harbor KRAS^G12V; however, the molecular mechanism by which iMDK induces apoptosis remains unknown. In addition, due to its hydrophobic structure, iMDK is insoluble in water, making iMDK unsuitable for clinical translation. To understand the molecular mechanism, we conducted RNA-seq analysis to identify genes that are regulated by iMDK in H441 cells. RNA-seq data analysis indicated that iMDK activated the ATF3-CHOP (DDIT3)-mediated apoptotic pathway. iMDK did not induce apoptosis in ATF3 or CHOP CRISPR knockout H441 cells, indicating that iMDK induced apoptosis through the ATF3-CHOP pathway. Notably, iMDK also activated ATF3 and induced apoptosis in both sotorasib (KRAS^G12C inhibitor)-naïve and resistant H358 bronchioalveolar carcinoma cells that harbor KRAS^G12C. To administer iMDK in water, we encapsulated iMDK in multiple lipid or polymer nanoparticles that could be suspended in water. Importantly, iMDK that was encapsulated in DPPC/DOTAP/DSPE-PEG/Cholesterol lipid nanoparticles but not DPPC/DPPG/DSPE-PEG/Cholesterol or PEI-PEG-LinA nanoparticles induced apoptosis in H441 cells in vitro. Intraperitoneal injection of water-soluble iMDK lipid nanoparticles (DPPC/DOTAP/DSPE-PEG/Cholesterol) significantly reduced the growth of H441 xenografts without inducing liver toxicity in vivo. These results suggest that water-soluble iMDK lipid nanoparticle delivery is effective for treating subtypes of KRAS mutant lung cancers that retain the ATF3-mediated apoptotic pathway.