Selective EGFR Inhibition: The Promise of E-191 in Overcoming NSCLC Resistance

The study focuses on the development of a new drug, E-191, designed to combat resistance in non-small cell lung cancer (NSCLC) patients with specific EGFR mutations. The first generation EGFR inhibitors, such as gefitinib and erlotinib, are usually effective initially but resistance often develops due to the EGFR T790M mutation. E-191 is an irreversible EGFR inhibitor that shows high potency against EGFR mutations while sparing the wild type EGFR, which could reduce side effects.

The drug's effectiveness was tested in various cell lines, including NCI-H1975 and HCC827, which have EGFR mutations, and A431, which has the wild type EGFR. E-191 showed strong anti-proliferative activity in the mutated cell lines with an IC50 of 22 nM and 1.9 nM respectively, and significantly less activity in the A431 cell line with an IC50 of 531 nM.

In vivo studies using tumor xenograft models demonstrated that E-191 significantly inhibited tumor growth in the NCI-H1975, HCC827, and Ba/F3 models, which all have EGFR mutations, and had a much less pronounced effect on the A431 model. Western blot analysis confirmed that E-191's anti-tumor effect was due to its inhibition of the EGFR signaling pathway.

The findings suggest that E-191 is a promising candidate for treating NSCLC that has become resistant to first-line EGFR inhibitors. The study was presented at the American Association for Cancer Research Annual Meeting in 2018.