Destabilized 3UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

Abstract

Breast, lung, and colorectal cancer resistance to molecular targeted therapy is a major challenge and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. In ERBB2+ cancers regardless of the tissue of origin, ERBB2 is the driver oncogene of resistance. We discovered that the ERBB2+ cancers are enriched with poly U sequences on their 3UTR AU rich elements which are mRNA stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA stabilizing sequences to unstable forms and specifically controlled and degraded ERBB2 transcript and protein across multiple cancer types both in the wildtype and drug resistance settings in vitro and in vivo, offering a unique novel modality to control ERBB2 and other pervasive oncogenic signals where other therapies fail. One-Sentence SummaryEngineered destabilized 3UTR ARE of ERBB2 degrades ERBB2 in many cancer types and controlled resistance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/503914v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@139d8dborg.highwire.dtl.DTLVardef@cc1fd3org.highwire.dtl.DTLVardef@13d9086org.highwire.dtl.DTLVardef@db69bf_HPS_FORMAT_FIGEXP M_FIG A. Depiction represents multiple ERBB2 expressing cancer cells with stable 3UTR ARE and the signaling cascade known to cause chemo resistance. B. Depiction of the engineered destabilized 3UTR ARE of ERBB2 and the destabilization and degradation of the ERBB2 transcript, protein and kinases involved in mediation of drug resistance C_FIG