Abstract
Abstract Background: Inhibition of thymidylate synthase (TS) results in a transient compensatory “flare” in thymidine salvage pathway activity which is measureable with 18F-thymidine (FLT) positron emission tomography (PET) at 2 hrs of exposure to therapy. Here we examine the predictive value of the FLT-PET measured “flare” for NSCLC sensitivity to pemetrexed, a commonly used TS inhibitor, in a preclinical model. Experimental Design: Resistance to pemetrexed therapy was induced in two sensitive human NSCLC cell lines, H460 and H1299, by overexpressing TS. TS overexpression was confirmed with RT-PCR and Western blotting and pemetrexed-resistance confirmed with IC50 assays. The presence of a pemetrexed-induced DNA salvage pathway “flare” was then measured using 3H-thymidine in both pemetrexed-sensitive (H460 and H1299) and resistant (H460R and H1299R) lines in vitro, as well as inherently resistant NSCLC cell lines CALU6, H522, H650, H661, H820, H1838, and validated with FLT-PET in vivo using H460 and H460R xenografts. Results: Overexpression of TS induced resistance to pemetrexed in the H460 and H1299 with IC50 for H460, H1299, H460R and H1299R measured as 0.141 μM, 0.656 μM, 22.842 μM, 213.120 μM, respectively. Significant increases in DNA salvage pathway activity (“flare”) was observed at 2hrs of therapy in the pemetrexed-sensitive H460 and H1299 lines but not the resistant H460R and H1299R, CALU6, H522, H650, H661, H820, H1838 cell lines in vitro using 3H-thymidine assays. Similarly, FLT “flare” was observed in the pemetrexed-sensitive H460 xenograft tumors but not the pemetrexed-resistant H460R xenograft tumors with post-therapy increases in measured FLTmax of 58% (STD 12.1) and 10.8% (STD 7.3) respectively. Conclusions: FLT-PET imaging of TS inhibition may provide an early indicator of NSCLC sensitivity to pemetrexed. Citation Format: Xiao Chen, Yizeng Yang, Sharyn Katz. Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1783. doi:10.1158/1538-7445.AM2017-1783
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