Destabilized 3'UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+cancer models

Breast, lung, and colorectal cancer resistance to molecular targeted therapy is a major challenge that unfavorably impacts clinical outcomes leading to hundreds of thousands of deaths annually. In ERBB2+ cancers regardless of the tissue of origin, many ERBB2+ cancers are resistant to ERBB2-targeted therapy. We discovered that ERBB2+ cancer cells are enriched with poly U sequences on their 3'UTR which are mRNA-stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA-stabilizing sequences to unstable forms that successfully overwrote and outcompeted the endogenous ERBB2 mRNA-encoded message and degraded ERBB2 transcripts which led to the loss of the protein across multiple cancer cell types both in the wildtype and drug-resistance settings in vitro and in vivo, offering a unique safe novel modality to control ERBB2 mRNA and other pervasive oncogenic signals where current targeted therapies fail.

Automated summary

Resistance to targeted therapy is a challenge in breast, lung, and colorectal cancers, leading to a large number of deaths annually. We found that ERBB2+ cancer cells have mRNA-stabilizing sequences on their 3'UTR. By manipulating these sequences, we successfully degraded ERBB2 transcripts and reduced protein levels in various cancer cell types, providing a new approach to control oncogenic signals where current therapies fail.