Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827. We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo. Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF. These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer.
Highlights
Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related death worldwide
These results indicate that transient blockade of phosphoinositide 3kinase (PI3K)/Akt pathway by PI-103 and gefitinib could overcome hepatocyte growth factor (HGF)-mediated resistance to Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) by inducing apoptosis in EGFR mutant lung cancer
We showed that transient blockade of PI3K/Akt pathway by PI3K inhibitor and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in both in vitro and in vivo models
Summary
Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related death worldwide. Non–small cell lung cancer (NSCLC) accounts for nearly 80% of lung cancer cases. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Receptor (EGFR)-mediated downstream pathways, including mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3kinase (PI3K)/Akt, and to show favorable activity in NSCLC patients with mutant EGFR [1]. Recent phase III clinical trials showed that patients with EGFR mutant NSCLC had superior outcomes with gefitinib treatment, compared with standard first-line cytotoxic chemotherapy [2,3]. The patients develop acquired resistance to EGFR-TKIs almost without exceptions within a couple of years [4]. 20% to 25% patients with EGFR activating mutations show intrinsic resistance to EGFR-TKIs
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