Abstract
Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.
Highlights
1.7 million new cancer cases and 0.6 million cancer deaths are projected to occur in the United States in 2013, and lung cancer is responsible for 26% and 28% of all female and male cancer deaths, respectively [1]
To assess effects on cellular proliferation, rapamycin and pemetrexed were tested at concentrations that are clinically achievable in a series of four Non-small cell lung cancer (NSCLC) cell lines that vary in status of molecular targets such as EGFR and
S6 is phosphorylated by S6K, which is a direct substrate of mammalian target of rapamycin (mTOR). 4E-binding protein 1 (4E-BP1) is regulated by mTOR and inhibits 5′-cap-dependent mRNA translation by binding and inactivating eukaryotic translation initiation factor 4E that is involved in the mRNAribosome binding step of eukaryotic protein synthesis
Summary
1.7 million new cancer cases and 0.6 million cancer deaths are projected to occur in the United States in 2013, and lung cancer is responsible for 26% and 28% of all female and male cancer deaths, respectively [1]. Platinum-based chemotherapy regimens given as first-line treatment to advanced NSCLC patients with a good performance status have plateaued in overall response rate (25%-35%), median survival (8-10 mo.), one-year survival (30%-40%), and two-year survival (10%-15%) [3]. Pemetrexed was approved by the US Food and Drug Administration (FDA) as a firstline therapy for advanced non-squamous NSCLC patients when combined with cisplatin and as a maintenance therapy for patients with advanced non-squamous NSCLC who do not experience disease progression after platinum-based chemotherapy [5, 6]. Pemetrexed as a single-agent is a standard treatment for recurrent NSCLC patients who have previously received platinum-based chemotherapy, but the overall response rate is less than 10% and resistance to pemetrexed eventually develops [4]. Increased expression of TS confers resistance to pemetrexed in lung cancer cells in vitro [8, 9] and is a predictive factor for poor response to pemetrexed in patients [10], indicating that inhibition of TS expression may be beneficial for overcoming resistance to pemetrexed
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