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 KRASG12V; 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 (KRASG12C inhibitor)-naïve and resistant
H358 bronchioalveolar carcinoma cells that harbor KRASG12C. 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.