Oncotarget

Research Papers:

Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation

Benjamin Y. Owusu, Shantasia Thomas, Phanindra Venukadasula, Zhenfu Han, James W. Janetka, Robert A. Galemmo, Lidija Klampfer _

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Abstract

Benjamin Y. Owusu1, Shantasia Thomas1, Phanindra Venukadasula1, Zhenfu Han2, James W. Janetka2, Robert A. Galemmo Jr1 and Lidija Klampfer1

1Department of Oncology Southern Research, Birmingham, AL, 35205 USA

2Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine St. Louis, MO 63110 USA

Correspondence to:

Lidija Klampfer, email: klampfer@southernresearch.org

Keywords: HGF, MET, NSCLC

Received: January 13, 2017    Accepted: May 03, 2017    Published: May 29, 2017

ABSTRACT

Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment.

The tumor microenvironment plays a major role in resistance to anticancer therapy. We demonstrated that fibroblasts block the response of MET-amplified NSCLC cells to the MET kinase inhibitor, JNJ38877605 in an HGF-dependent manner. Thus, MET-amplified NSCLC cells become addicted to HGF upon pharmacological inhibition of MET. HGF restored phosphorylation of MET, EGFR and RON, and maintained pro-survival AKT and ERK signaling in MET-inhibited cells.

We developed a small molecule inhibitor of pro-HGF activation, SRI31215, which acts as a triplex inhibitor of the pro-HGF activating proteases matriptase, hepsin and HGF activator (HGFA). SRI31215 blocked crosstalk between tumor cells and fibroblasts and overcame fibroblast-mediated resistance to MET inhibition by preventing fibroblast-mediated reactivation of AKT and ERK signaling. Structurally unrelated triplex inhibitors of matriptase, hepsin and HGFA that we developed in parallel showed similar biological activity.

Our data suggest that simultaneous inhibition of HGF and MET is required to overcome resistance to MET inhibitors in MET-amplified NSCLC cells. This provides a rationale for the development of novel combination therapeutic strategies for the treatment of NSCLC patients with MET amplification.

Author Information

Benjamin Y. Owusu

Shantasia Thomas

Phanindra Venukadasula

Zhenfu Han

James W. Janetka

Robert A. Galemmo

Lidija Klampfer
Primary Contact  _


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