Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging

Xiao Chen; Yizeng Yang; Sharyn Katz

doi:10.18632/oncotarget.19751

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Research Papers:

Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging

Xiao Chen, Yizeng Yang and Sharyn Katz _

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Oncotarget. 2017; 8:82705-82713. https://doi.org/10.18632/oncotarget.19751

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Abstract

Xiao Chen1,2, Yizeng Yang3 and Sharyn Katz1

1Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

2Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China

3Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Correspondence to:

Sharyn Katz, email: [email protected]

Keywords: FLT, PET, pemetrexed, lung cancer, flare

Received: April 19, 2017 Accepted: June 01, 2017 Published: July 31, 2017

ABSTRACT

Introduction: Inhibition of thymidylate synthase (TS) results in a transient compensatory “flare” in thymidine salvage pathway activity measureable with ¹⁸F-thymidine (FLT)- positron emission tomography (PET) at 2hrs. of therapy which may predict non-small cell lung cancer (NSCLC) sensitivity to TS inhibition.

Materials and Methods: Resistance to TS inhibition by pemetrexed was induced in NSCLC cell lines H460 and H1299 through TS overexpression. TS overexpression was confirmed with RT-PCR and Western blotting and pemetrexed resistance confirmed with IC₅₀ assays. The presence of a pemetrexed-induced thymidine salvage pathway “flare” was then measured using ³H-thymidine in both pemetrexed sensitive (H460 and H1299) and resistant (H460R, H1299R, CALU-6, H522, H650, H661, H820, H1838) lines in vitro, and validated with FLT-PET in vivo using H460 and H460R xenografts.

Results: Overexpression of TS induced pemetrexed resistance with IC₅₀ for H460, H1299, H460R and H1299R measured as 0.141 μM, 0.656 μM, 22.842 μM, 213.120 μM, respectively. Thymidine salvage pathway ³H-thymidine “flare” was observed following pemetrexed in H460 and H1299 but not H460R, H1299R, CALU-6, H522, H650, H661, H820 or H1838 in vitro. Similarly, a FLT “flare” was observed in vivo following pemetrexed therapy in H460 but not H460R tumor-bearing xenografts.

Conclusions: Imaging of TS inhibition is predictive of NSCLC sensitivity to pemetrexed.

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Research Papers:

Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging

Abstract