Polyomavirus middle T (PyVmT) transforms cells through phosphatidylinositol 3-kinase (PI3K). Overexpression of ErbB2/ErbB3 heterodimers, potent activators of PI3K, occurs in PyVmT-driven mouse mammary tumors, but without known cause and consequence. Inhibition of ErbB2 with lapatinib, or genetically engineered loss of ErbB3, decreased PI3K signaling and tumor growth in mice, suggesting ErbB2/ErbB3 is required by PyVmT. ErbB2/ErbB3 formed signaling complexes containing PyVmT, p85 and Src. EZN-3920, a novel high-affinity oligonucleotide targeting ErbB3 transcripts, impaired ErbB3 expression in vivo, decreased PI3K signaling, cell survival, and growth of tumors, and improved response to lapatinib. Therefore, PyVmT utilizes ErbB2/ErbB3 overexpression to drive PI3K signaling. Furthermore, the challenge of ErbB3 as a kinase-inactive therapeutic target can be overcome by targeting ErbB3 mRNA transcripts in vivo. Significance

Given the widespread use of, and knowledge gained from the MMTV-PyVmT transgenic mouse breast cancer model, understanding how PyVmT utilizes existing cell signaling programs is necessary to interpret how results impact our understanding/treatment of human breast cancers. We found that ErbB2/ErbB3 heterodimers were a necessary part of PyVmT signaling complexes involving Src and PI3K, and that PyVmT depends on ErbB3 in the breast epithelium for PI3K activity and tumor growth. Because ErbB3 harbors a weak/inactive tyrosine kinase, therapeutic anti-ErbB3 interventions present with challenges. Further, anti-ErbB3 antibodies that block ligand interaction with ErbB3 do not alter ligand-independent ErbB3 signaling. However. these challenges were overcome using high-affinity oligonucleotides targeting ErbB3 mRNA. Use of the oligonucleotide EZN-3920 effectively reduced ErbB3 expression, inhibited PyVmT tumor growth, and improved the response of tumors to lapatinib. These results support oligonucleotide knock-down of targets as potential therapeutic strategy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-10.