Abstract
Purpose: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA-damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in preclinical model systems.Experimental Design: PAPSS1 expression and cisplatin IC50 values were assessed in 52 lung adenocarcinoma cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed.Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in lung adenocarcinoma. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared with control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy.Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes. Clin Cancer Res; 23(21); 6555-66. ©2017 AACR.
Highlights
IntroductionThe majority of non–small cell lung cancer (NSCLC) patients are diagnosed with an inoperable disease and are given platinum-based chemotherapy or molecularly targeted treatments
The majority of non–small cell lung cancer (NSCLC) patients are diagnosed with an inoperable disease and are given platinum-based chemotherapy or molecularly targeted treatments.Note: Supplementary data for this article are available at Clinical Cancer Research Online.Ó2017 American Association for Cancer Research.Platinum-based regimens have been the mainstay treatment for NSCLC for over 30 years with response rates of 30%–33% [1]
These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients
Summary
The majority of non–small cell lung cancer (NSCLC) patients are diagnosed with an inoperable disease and are given platinum-based chemotherapy or molecularly targeted treatments. Platinum-based regimens have been the mainstay treatment for NSCLC for over 30 years with response rates of 30%–33% [1]. Depending on the tumor microenvironment, some cell populations within the tumor will be exposed to sublethal doses of chemotherapy, contributing to poor response and eventually, tumor recurrence. If these cells were to be sensitized to platins, they would not be able to survive even suboptimal doses of the treatment and contribute to the development of drug-resistant tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
