Abstract 4362: Silencing of PAPSS1 (3’-phosphoadenosine 5’-phosphosulfate synthase 1) potentiates cisplatin activity against non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers with two out of three patients having an inoperable disease at the time of diagnosis. Standard first-line treatments for these patients are combinations of two chemotherapy drugs, with one typically being cisplatin. Despite the use of new targeted therapies and attempts to develop triplet combinations, the overall 5-year survival rate for NSCLC remains below 20%. A genome-wide siRNA (small-interfering RNA) screen was performed in A549 cells to rapidly identify individual genes that, when silenced, would enhance cisplatin activity. One of the top targets that emerged from the screen was 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthase 1 (PAPSS1), a bi-functional enzyme that synthesizes PAPS, the universal sulfate donor. Here, we evaluated PAPSS1 as a cisplatin-potentiating gene target in NSCLC. The effect of PAPSS1 inhibition on cisplatin activity was assessed across eight different chemo-naive NSCLC cell lines. Cells were transfected with lipid-complexed siRNA targeting PAPSS1 and treated with various concentrations of cisplatin 24 hours later. The dose response was determined based on viable cell count 72 hours post-treatment using the IN Cell Analyzer. Gene knockdown was confirmed via qPCR and Western blot analysis. Silencing of PAPSS1 resulted in significant reduction in the IC50 of cisplatin in five chemo-naive NSCLC cell lines at siRNA concentrations that would not induce significant lipid toxicity over a 72-hour culture period. For example, PAPSS1 silencing was associated with a 5-fold decrease (p Citation Format: Ada Leung, Brian Kwok, Daniel Ricaurte, Amith Ahluwalia, Mohammed A. Qadir, Marcel B. Bally. Silencing of PAPSS1 (3’-phosphoadenosine 5’-phosphosulfate synthase 1) potentiates cisplatin activity against non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4362. doi:10.1158/1538-7445.AM2013-4362