All ETDs from UAB

Advisory Committee Chair

Lidija Klampfer

Advisory Committee Members

Upender Manne

Ralph Sanderson

Tim Townes

Bo Xu

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The tumor microenvironment plays a key role in tumor progression and therapeutic resistance. Hepatocyte growth factor (HGF), commonly expressed by cancer-associated fibroblasts, mediates signaling via its receptor, MET, and promotes survival, proliferation, migration and invasion of cancer cells. In addition, HGF dependence has emerged as a hallmark of therapeutic resistance. HGF is secreted as an inactive precursor, pro-HGF, which requires proteolytic cleavage and processing to form the mature, active HGF. This is the rate-limiting step in the HGF/MET signaling pathway and it is achieved by one of the serine proteases, matriptase, hepsin and HGF activator (HGFA). At Southern Research, we developed SRI31215, a novel small molecule triplex inhibitor of the pro-HGF-activating serine proteases. We demonstrated that SRI31215 inhibits HGF-dependent, fibroblast-induced, MET activation, epithelial-mesenchymal transition (EMT) and migration of cancer cells. In addition, SRI31215 blocks autocrine and paracrine MET activation and overcomes resistance to anti-EGFR therapy, such as cetuximab and gefitinib in colon cancer cells. Acquired resistance to EGFR inhibitors is not only mediated by overproduction of HGF, but is frequently associated with MET amplification. MET-amplified non-small cell lung cancer (NSCLC) cells do not respond to EGFR inhibitors, but are highly sensitive to MET inhibition. We demonstrated that both recombinant HGF and pro-HGF-producing fibroblasts protect MET-amplified NSCLC cells from anti-MET therapy by restoring proliferative and prosurvival ERK and AKT signaling. SRI31215 overcomes fibroblast-mediated resistance to anti-MET therapy in MET-amplified lung cancer cells. These findings underscore the importance of inhibiting both HGF and MET to overcome resistance to MET-targeted therapy in MET-amplified NSCLC cells. Taken together, our findings indicate that SRI31215 blocks HGF-dependent, tumor-promoting crosstalk between cancer cells and fibroblasts and overcomes primary and acquired resistance to targeted therapy. These data indicate that targeting both the cancer cells and the abnormal tumor microenvironment is likely to be required to prevent therapeutic resistance.

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