Abstract 2753: The addition of low dose 17-DMAG to BIBW-2992 effectively inhibits lung cancer cells with acquired resistance by T790M mutation

Abstract

Abstract The majority of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is caused by secondary T790M mutation. We established gefitinib or erlotinib-resistant cells which acquired different proportions of T790M from PC-9 cells with activating EGFR mutation. Anti-cancer effects of EGFR modulation and strategies overcoming resistance were investigated. The amount of T790M and EGFR gene copy number were proportional to increase of resistance. BIBW-2992, an irreversible EGFR-TKI, could suppress the growth and survival of cells harboring lower level of T790M while it failed in cells with higher level of T790M although p-EGFR was completely down-regulated in both, suggesting blocking of phosphorylation of EGFR is not sufficient to inhibit these cells. However, EGFR siRNA treatment could inhibit cell growth regardless of T790M level and resistance showing that EGFR dependency would be persistent. 17-DMAG, a HSP90 inhibitor, also effectively controlled both resistant cells. Considering a report showing that a HSP90 inhibitor was not clinically effective possibly because of inadequate dose, the efficacy of low dose 17-DMAG was examined. Interestingly, we found that combined treatment of BIBW-2992 with low dose 17-DMAG was very effective even in cells with higher level of T790M although either of both showed no activity in single treatment suggesting it would be one of promising strategies with immediate clinical implications overcoming T790M-mediated resistance. Further investigations on exact mechanism should be pursued even though capability of HSP90 inhibitor to modulate NF-kB signaling can be one of possible explanations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2753. doi:1538-7445.AM2012-2753