Neuropilin 1 confers resistance to Her1/2 targeted therapies via epithelial to mesenchymal transition in metastatic breast cancer
Abstract
Inhibition of the ErbB family of receptor tyrosine kinases (i.e. Her1 and Her2) has been a testament to the potential of molecular targeted therapies of cancer. Though these therapies thrive initially in the treatment of breast cancer, they eventually fall victim to drug resistance. The driving mechanism of this resistance is Epithelial-Mesencynchmal Transition (EMT), a process by which polarized epithelial cells become fibroblast-like through alterations in gene expression. A commonly upregulated gene in EMT and Her1/2 inhibitor resistance is Neuropilin 1 (Nrp1). Nrp1 is classically known as a transmembrane pro-angiogenic co-receptor of Semaphorin 3A and vascular endothelial growth factors, thus illustrating its importance in development, tumorigenesis, and metastasis. While full-length Nrp1 is implicated in tumorigenesis and EMT, little is known about its role in acquired resistance to chemotherapies. Here, we hypothesize that expression of Nrp1 confers resistance to Her1/2 inhibition in breast cancer. We have recently found constitutively activated Erk in Her1/2 therapy-resistant cells, and that these resistant lines have elevated Nrp1 expression. Furthermore, this Erk activation is recapitulated in our Nrp1 overexpression systems. Further, dose-response and 3D growth assays, as well as in vivo bioluminescent imaging have revealed that overexpression of Nrp1 is sufficient to drive resistance to Lapatinib in our Her1-transformed cells and in the Her2-amplified SkBr3 cancer cells. We aim to deplete Nrp1 in these systems to determine if this molecule is necessary to drive Her1/2 resistance in these models. This information will provide a novel target for breast cancers that have acquired resistance to targeted therapies as well as provide potential combinatorial therapeutic options to overcome metastatic breast cancer.
Degree
M.S.
Advisors
Wendt, Purdue University.
Subject Area
Pharmacy sciences
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