Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models. Experimental Design/ Treatment with LY2801653 showed tumor growth inhibition in tumor cell lines and patient-derived tumor xenograft models as a single agent (37.4%-90.0% inhibition) or when used in combination with cisplatin, gemcitabine, or erlotinib (66.5%-86.3% inhibition). Mechanistic studies showed that treatment with LY2801653 inhibited the constitutive activation of MET pathway signaling and resulted in inhibition of NCI-H441 cell proliferation, anchorage-independent growth, migration, and invasion. These in vitro findings were confirmed in the H441 orthotopic model where LY2801653 treatment significantly inhibited both primary tumor growth (87.9% inhibition) and metastasis (64.5% inhibition of lymph node and 67.7% inhibition of chest wall). Tumor-bearing animals treated with LY2801653 had a significantly greater survival time (87% increase compared with the vehicle-treated mice). In the MET-independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis. Collectively, these results support clinical evaluation of LY2801653 in NSCLCs and suggest that differences in the MET activation of tumors may be predictive of response.
Highlights
Lung cancer is the leading cause of cancer-related death in many countries, including the United States [1]
In the MET-independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis. Collectively, these results support clinical evaluation of LY2801653 in non–small cell lung cancer (NSCLC) and suggest that differences in the MET activation of tumors may be predictive of response
The prognosis of patients with advanced lung cancer remains poor, and recent studies show that conventional therapies may have reached a therapeutic plateau as evidenced by the 5-year survival rate for NSCLCs, which remains at 15% [2, 3]
Summary
Lung cancer is the leading cause of cancer-related death in many countries, including the United States [1]. The prognosis of patients with advanced lung cancer remains poor, and recent studies show that conventional therapies may have reached a therapeutic plateau as evidenced by the 5-year survival rate for NSCLCs, which remains at 15% [2, 3]. The potential promise of this strategy has been illustrated by the clinical benefits associated with EGF receptor (EGFR) inhibitors gefitinib and erlotinib in a subset of patients with NSCLCs harboring EGFR mutations [4]. The response rate to EGFR inhibitors is only 10% for patients without EGFR mutation, and even in responders, treatment response may be of limited durability due to the acquisition of resistance to gefitinib or erlotinib. The limited therapeutic options currently available for patients with advanced lung cancer create a pressing need to identify new therapeutic targets
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