KRAS mutations have wide-spread prevalence in human cancers nowadays. KRASG12C mutations occur in 16% of lung adenocarcinomas, making them one of the most frequent activating genetic alterations in lung cancer. The mis-sense mutation of KRAS at codon 12 aberrantly activates the protein into a hyperexcitable state. Attenuating its GTPase activity results in accretion of GTP-bound activated KRAS and activation of downstream signaling pathways. KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity disabled. Cancer-causing mutations impair the GTPase activity of RAS, causing it to accumulate in the activated state. KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.
In this study, Piro Lito characterize a novel compound, ARS853, designed to bind KRASG12C with high affinity. Fortunately, treatment of KRASG12C-mutant lung cancer cells with ARS853 reduces the level of GTP-bound KRAS by more than 95%. This causes decreased phosphorylation of CRAF, ERK (extracellular signal–regulated kinase), and AKT. Moreover, ARS-853 inhibits proliferation with an IC50 of 2.5 μM, which is similar to its IC50 for target inhibition. ARS853 (10 μM) inhibits effector signaling and cell proliferation to varying degrees in six KRASG12C mutant lung cancer cell lines, but not in non-KRASG12C models. Similarly, ARS853 completely suppresses the effects of exogenous KRASG12C expression on KRAS-GTP levels, KRAS-BRAF interaction, and ERK signaling. Inhibitor treatment also induces apoptosis in four KRASG12C mutant cell lines. Thus, ARS853 selectively reduces KRAS-GTP levels and RAS-effector signaling in KRASG12C-mutant cells, while inhibiting their proliferation and inducing cell death.