Novel Potent EGFR-JAK3 Dual-Target Inhibitor that Overcomes KRAS Mutation Resistance in Colorectal Cancer

Abstract

Background: In-depth and clear mechanistic study is a prerequisite for new drugs to enter clinical research.

Methods: New chemical entity BY4008 was identified by our lab as a novel and highly potent EGFR and JAK3 dualtarget inhibitor. A cell-based test exhibited strong antiproliferative activities against SW620 and HCT116 colon cancer cells harboring KRAS mutation with IC₅₀ of nanomolar potency. Furthermore, acridine orange/ethidium bromide (AO/EB), Hematoxylin-Eosin (H&E) and DAPI staining assays and flow cytometry analyses indicated that BY4008 has the function of pro-apoptosis and arresting the cell cycle. In addition, BY4008 inhibited the autophosphorylation of EGFR and blocked the activation of downstream signaling and the JAK-STAT3 pathway.

Results: Meanwhile, a decreased level of reactive oxygen species (ROS) and an increased level of malondialdehyde (MDA) in SW620 and HCT116 cells were observed after exposure to BY4008.

Conclusion: In summary, this study provides an important structural basis and mechanistic study for future effective treatment of colorectal cancer.

Keywords: EGFR; JAK3; KRAS mutation; clinical research; colorectal cancer; dual-target inhibitor.