Therapeutic targeting of sphingosine kinase 2 in tyrosine kinase inhibitor resistance and non-small cell lung cancer tumorigenicity

S.M. Nasifuzzaman, N. Dube, K. Lam, R.J. Hillwig and N. Puri
University of Illinois, Illinois, United States

Poster stand number: W128

Keywords: NSCLC, Sphingosine kinase 2, Tyrosine kinase Inhibitor , Tumorigenicity

Tyrosine Kinase Inhibitors (TKIs) such as Erlotinib (ER) and Osimertinib (OR) are currently being used to treat lung cancer patients with EGFR mutations; however, patients develop resistance to these drugs within 6-18 months. Sphingosine kinase 2 (SK2), upregulated in Lung Cancer, phosphorylates sphingosine to sphingosine-1-phosphate (S1P), promoting cell proliferation. However, the role of SK2 in TKI resistance is unknown. We hypothesize that SK2 may be involved in inducing TKI- resistance in NSCLC cells and is positively correlated with tumor progression. We studied SK2 in drug resistant (OR and ER) and parental NSCLC cells. In drug resistant cells, qPCR and western blotting showed that SK2 was upregulated by 1.3-4.3 fold compared to parental. These results suggest that SK2 may play a role in TKI resistance. MTT assay data showed 71% inhibition of cell growth by OR and SK2 inhibitor in NSCLC cells. To analyze SK2 expression in cancer progression, IHC experiments performed on 60 early/44 late stage lung cancer patient sections showed upregulation of SK2 in late-stage lung cancer (p