EGFR is one of the oncogenic drivers in non-small-cell lung adenocarcinoma (NSCLC AC). EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib and afatinib, show remarkable single agent activity in NSCLC AC with EGFR mutations. However, a majority of the tumors develop resistance within twelve months. T790M secondary EGFR mutation and activation of alternative signaling pathways, such as MET, are the two most common resistance mechanisms.
To address this clinical challenge, we developed IMGN289, an EGFR antibody-drug conjugate consisting of the novel J2898A antibody (Ab), which selectively binds to and inhibits EGFR-driven tumor cell growth, conjugated to the maytansinoid DM1, a potent anti-microtubule agent, via the SMCC thioether linker. IMGN289 showed significantly enhanced cytotoxic activity, relative to cetuximab or unconjugated J2898A, against tumor cell line models that are dependent on EGFR signaling (Chittenden et al., AACR 2013). To evaluate the ability of IMGN289 to overcome mechanisms of EGFR TKI resistance, IMGN289 activity was tested in erlotinib-resistant EGFR-mutant cell lines which overexpressed MET (HCC827-ER) or carry the T790M EGFR mutation (HCC827-EPR) (Suda et al., Clin Cancer Res 2010). Despite variable levels of EGFR expression in these cell lines, (193,000, 32,500 and 422,000 antigens per cell in HCC827, HCC827-ER and HCC827-EPR, respectively), IMGN289 showed comparable cytotoxic activities against these cell lines in vitro. In addition to MET overexpression, the MET pathway can also be activated by HGF, the MET ligand. While addition of HGF made the HCC827 cell line resistant to EGFR TKIs (Yano et al., Cancer Res 2008) and decreased growth inhibition by cetuximab, IMGN289 activity was unaffected. Additionally, we generated an erlotinib-resistant HCC827-ER-E4 cell line by exposing the EGFR-mutant HCC827 cells to increasing concentrations of erlotinib for ∼6 months, followed by subcloning. The HCC827-ER-E4 cell line expressed mesenchymal markers and acquired a mesenchymal phenotype. It expressed lower levels of EGFR, HER3 and MET compared to the parental cell line and showed no loss of PTEN. In the presence of erlotinib, HCC827-ER-E4 cells retained high levels of pAKT and pERK, suggesting that activation of alternative signaling pathways may be responsible for the erlotinib resistance. In vitro cytotoxic assays showed that IMGN289 was equally cytotoxic to the parental and the HCC827-ER-E4 cell line.
In conclusion, IMGN289 demonstrated EGFR-targeted cytotoxicity against NSCLC cell lines that harbor some of the most common mechanisms of resistance to EGFR TKIs. IMGN289 represents a promising novel candidate for treatment of EGFR-expressing NSCLC AC that has acquired resistance to EGFR TKIs.
Citation Format: Yulius Y. Setiady, Ling Dong, Anna Skaletskaya, Jan Pinkas, Robert J. Lutz, John M. Lambert, Thomas Chittenden. IMGN289, an EGFR-targeting antibody-drug conjugate, is effective against tumor cells that are resistant to EGFR tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4513. doi:10.1158/1538-7445.AM2014-4513