Targeting Sorting Nexins to Treat ErbB Dependent Breast Cancer

Abstract

EGFR is one of the most studied oncogenes in human biology with roles in proliferation, growth, and metastasis. This intense study has led to the development of a range of targeted therapeutics including small molecule tyrosine kinase inhibitors and monoclonal antibodies. These drugs are excellent at blocking activation and the kinase function of wtEGFR and many common EGFR mutants. These drugs have significantly improved patient outcomes with tumors including head and neck, glioblastoma, colorectal, and non-small cell lung cancer. However, these therapies are ineffective for the treatment of triple negative breast cancer (TNBC) even though about half of patients present with an overexpression of EGFR. In TNBC, EGFR is subjected to alternative trafficking which drives the nuclear localization of the receptor. In the nucleus, EGFR interacts with several proteins to activate transcription, DNA repair, migration, and chemoresistance. Previous work in our lab has demonstrated that blocking retrograde trafficking in TNBC cells significantly reduces EGFR driven oncogenic phenotypes. However, this retrograde trafficking inhibitor, Retro-2, blocks all retrograde trafficking with no specificity to EGFR. We then analyzed the retrograde trafficking of EGFR in TNBC and determined that the interaction between EGFR and SNX1 was a critical step for EGFR nuclear localization. We therefore developed a therapeutic peptide, cSNX1.3, that blocks the interaction of EGFR and SNX1 to inhibit the retrograde trafficking of EGFR. cSNX1.3 eliminates nuclear EGFR and reduces EGFR driven oncogenic phenotypes in vitro. Using a transgenic mouse model of EGFR driven breast cancer, we found that cSNX1.3 significantly reduced tumor growth and induces regression in several animals.