Targeting Oncogenic EGFR and HER2 Mutations with AP32788: A Preclinical Evaluation

The abstract discusses the effectiveness of various tyrosine kinase inhibitors (TKIs) against different mutations in non-small cell lung cancer (NSCLC). Currently, erlotinib, gefitinib, and afatinib are approved for common EGFR mutations, but there are no approved treatments for less common mutations or HER2 mutations. AP32788 is highlighted as a selective inhibitor that targets all oncogenic forms of EGFR and HER2, including those with exon 20 insertions, with greater potency than wild-type EGFR.

In vitro studies using Ba/F3 cell lines showed that while erlotinib and gefitinib were effective against only two common EGFR mutations, afatinib was effective against a few more. In contrast, AP32788 was found to be effective against all 20 EGFR and HER2 mutations tested, including those with exon 20 insertions, with IC50 values ranging from 2.4 to 35 nM.

Animal studies with mice bearing tumors with EGFR or HER2 exon 20 insertions demonstrated that AP32788, when administered orally, induced tumor regression at well-tolerated doses. The efficacy was linked to the inhibition of EGFR signaling within the tumor.

The abstract concludes that AP32788's ability to inhibit all tested activated forms of EGFR and HER2 more potently than wild-type suggests it could be an effective treatment for patients. A phase 1/2 clinical trial for AP32788 in NSCLC patients is being planned. The study was presented at the 107th Annual Meeting of the American Association for Cancer Research.