Abstract 2927: Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer

Abstract

Abstract Non-small-cell lung cancer (NSCLC) accounts for 80-85% of lung cancers and almost half of patients with newly diagnosed NSCLC have metastatic disease. Platinum-based chemotherapy regimens given as first-line treatment for advanced NSCLC patients with metastasis are standard but have modest response rates. Pemetrexed is well tolerated and inhibits several folate-dependent enzymes including thymidylate synthase, TS. Increased expression of TS confers resistance to pemetrexed in vitro and is a predictive factor for poor response to pemetrexed. Rapamycin is a mTOR inhibitor and suppresses protein synthesis. Here, we show that rapamycin decreases endogenous expression of TS in NSCLC cells. The combination of rapamycin and pemetrexed synergistically inhibits NSCLC cell proliferation and enhances the inhibition of 4E-binding protein 1 (4E-BP1) activation that is regulated by mTOR. Although pemetrexed as a single agent upregulated expression of TS, pretreatment with rapamycin suppressed pemetrexed-upregulated TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited the growth of NSCLC xenografts, which correlated with decreased mTOR activity and inhibition of pemetrexed-induced upregulated expression of TS. Based on these preclinical data, we have conducted a Phase I/II clinical trial combining rapamycin and pemetrexed in subjects with relapsed NSCLC. This regimen was well tolerated, and resulted in a 22% partial response rate that is above what is expected for response to single agent pemetrexed (9%). In biomarker analyses, pretreatment with rapamycin decreased the expression of TS in peripheral blood mononuclear cells, which correlated with increased progression free survival. Collectively, these studies identify rapamycin and pemetrexed as an effective combination in NSCLC, and suggest that rapamycin enhances the efficacy of pemetrexed by suppressing TS expression. Citation Format: Shigeru Kawabata, Chun-Te Chiang, Regan M. Memmott, Takefumi Komiya, Joell J. Gills, Phillip A. Dennis. Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2927. doi:10.1158/1538-7445.AM2014-2927