Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Abstract

Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models. A stable clone of PC-9/hHGF was less sensitive to erlotinib than the parental PC-9, and the addition of onartuzumab to erlotinib suppressed the proliferation of these cells in vitro. In PC-9/ hHGF xenograft tumors, onartuzumab or erlotinib alone minimally inhibited tumor growth; however, combining onartuzumab and erlotinib markedly suppressed tumor growth. The total MET protein level was decreased in PC-9/hHGF cells, because MET is constitutively phosphorylated by autocrine HGF, leading to its ubiquitination and degradation. Onartuzumab reduced phospho-MET levels, inhibited MET ubiquitination, and consequently restored MET protein levels. Moreover, in NSCLC clinical specimens harboring activating EGFR mutations, more than 30% of patients expressed high levels of HGF. Our findings raised the possibility that patients with NSCLC with EGFR mutations who express high levels of HGF may benefit from onartuzumab and erlotinib combination therapy, and that HGF can be a novel biomarker for selecting such patients.

Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC

“…Moreover, the presence of HGF can accelerate NSCLC‐cell resistance to EGFR TKIs by promoting clonal selection of a subpopulation of cells with c‐Met amplification . Preclinical studies in human lung cancer cell lines and lung tumor xenografts in transgenic mice have shown promising results with dual HGF/c‐Met and EGFR inhibition, including additive antitumor activity and restoration of EGFR‐TKI sensitivity . Taken together, these results indicate that combined EGFR and HGF/c‐Met inhibition is a promising strategy to overcome intrinsic and acquired resistance and thereby to improve the outcomes of NSCLC patients.…”

TC-N19, a novel dual inhibitor of EGFR and cMET, efficiently overcomes EGFR-TKI resistance in non-small-cell lung cancer cells

“…Therefore, the development of a new generation of EGFR-TKI and cMET inhibitors represents a critical strategy for overcoming EGFR-TKI resistance in NSCLC. 11, 12, 13, 14, 15, 16, 17, 18, 19 Unfortunately, EGFR-independent mechanisms of acquired resistance to AZD9291, a third-generation TKI, have already been reported in EGFR-E790M-positive NSCLC patients. 20 …”

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

“…The doses of ATL-1 used were based on another study, which showed significant inhibitory effects on tumor growth without noticeable toxicity [38]. In addition, the combination of erlotinib with other agents, showing even greater effects in inhibition of human cancer cells through multiple molecular mechanisms, have also been reported in other studies [54][55][56]. Our findings suggest that ATL-1 might sensitize or enhance the effect of erlotinib in the controlling human lung cancer cell growth or vice versa via targeting the tumor suppressor target genes PDK1 and EZH2 [57], and HOTAIR signaling axis.…”