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.
Highlights
Lung cancer remains a leading cause of cancerrelated deaths worldwide
Whereas MET-amplified lung cancer cells do not respond to epithelial growth factor receptor (EGFR) inhibition, their growth is strongly inhibited by MET tyrosine kinase inhibitors, confirming that these cells are addicted to MET signaling [13, 14]
In this study we demonstrated that hepatocyte growth factor (HGF), commonly produced by cancerassociated fibroblasts, confers resistance to MET kinase inhibitors in MET-amplified non-small cell lung cancer (NSCLC) cells
Summary
Oncogenic EGFR activation, commonly observed in non-small cell lung cancer (NSCLC), drives cell proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have become an important therapeutic modality for the treatment of NSCLC patients with EGFR mutations [1,2,3]. Innate or acquired resistance limits the efficacy of kinase inhibitors. The presence of KRas, BRaf and ERBB2 mutations predicts primary resistance to EGFR inhibitors [4, 5]. Acquired resistance to EGFR inhibitors has been associated most frequently with selection for secondary EGFR mutations, such as T790M in exon 20 [6, 7] and with MET amplification [8]. Drugs that target MET are in clinical trials to overcome MET-amplification-mediated resistance to EGFR inhibitors [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
