Date of Award
Dr. Adam B. Keeton, PhD
RAS is a prevalent oncogene that is mutated in 27% of human cancers. Gain-of-function RAS mutations activate multiple downstream pathways, including the RAS-RAF-MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. RAS proteins such as KRAS, a member of the RAS protein family, and their downstream effectors are attractive targets for cancer therapy since their mutations act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named MCI-062 was developed in Dr. Gary Piazza's Drug Discovery Research Center at the Mitchell Cancer Institute. As a potential pan-RAS inhibitor, MCI-062 is hypothesized to serve as a targeted therapy for RAS-mutant cancers regardless of mutation isoform, including all types of KRAS-mutant lung cancers. The inhibitory effects of MCI-062 were tested on the growth and proliferation of two non-small cell lung cancer cell lines, A549 and H358, using colony formation assays. The cells were plated onto 12-well plates, treated with varying concentrations of MCI-062, and then digitally imaged and analyzed. A549 cells have a KRASG13D mutation, while H358 cells have a KRASG12C mutation. The results indicate that MCI-062 effectively suppresses the growth and proliferation of both A549 and H358 cells despite their differing mutation isoforms, suggesting that MCI-062 successfully functions as a pan-RAS inhibitor.
Fu, Richard, "Applying MCI-062, A Novel Pan-RAS Inhibitor, To Treat KRAS-Mutant Lung Cancer" (2022). Undergraduate Theses . 32.