FTY720 is a sphingosine analogue drug that has been recently approved by FDA for the treatment of patients with refractory multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), and P- FTY720 is immune suppressive, which is required for its anti-MS activity. This proposal was designed to test a novel hypothesis that FTY720, but not its immunesuppressive form P-FTY720, suppresses NSCLC tumor growth by directly targeting I2PP2A/SET oncoprotein, leading to activation of PP2A, RIPK1-dependent programmed necrosis (necroptosis) and consequent tumor suppression. To test this hypothesis, two Specific Aims are proposed:
Aim 1 was designed to determine the roles and mechanisms by which binding I2PP2A/SET by FTY720 activates tumor suppressive PP2A.
Aim 2 was designed to determine the down- stream mechanisms by which targeting I2PP2A/SET by FTY720 induces cell death.
The studies proposed in this application will help identify a novel molecular target, I2PP2A/SET oncoprotein, and they will provide a first-in-class treatment option using an already FDA-approved drug, FTY720, for selectively targeting I2PP2A/SET, leading to NSCLC tumor suppression via induction of programmed necrosis, providing a mechanism-based precision therapeutic strategy for the treatment of this disease.
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