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

INTRODUCTION

Inhibition of thymidylate synthase (TS) results in a transient compensatory "flare" in thymidine salvage pathway activity measureable with F-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 IC assays. The presence of a pemetrexed-induced thymidine salvage pathway "flare" was then measured using H-thymidine in both pemetrexed sensitive (H460 and H1299) and resistant (H460R, H1299R, CALU-6, H522, H650, H661, H820, H1838) lines , and validated with FLT-PET using H460 and H460R xenografts.

RESULTS

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

CONCLUSIONS

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