Table 2:

PP2A activation in combination with other targeted therapies

Reference	Cancer	PP2A activating agent	Combination Therapy	Major Findings In addition to enhanced cell death in vitro with combination therapy vs. single agent
Alinari et al. Blood 2011	Mantle cell lymphoma	FTY720	Milatuzumab (mAb against CD74)	FTY720 increases sensitivity to milatuzumab by blocking CD74 lysosomal degradation resulting in increased CD74 abundance Combination treatment significantly increased overall survival in a SCID murine xenograft model of systemic MCL
Agarwal et al. Clin Cancer Res 2014	Chronic myeloid leukemia/ acute myeloid leukemia	OP449	Imatinib, nilotinib, ponatinib, dasatinib, AC220 (FLT3 inhibitor), JAK Inhibitor I, AraC	OP449 leads to decreased BCR-ABL phosphorylation and protein levels in CML cells OP449 treatment decreased STAT5, AKT and ERK phosphorylation and is selectively toxic to patient derived AML cells and has no effect on normal CD34+ cells OP449 enhances apoptotic response from targeted therapy in AML driven by FLT3 and JAK3 and increases AraC-induced cell death in AML cells with NRAS mutations
Gutierrez et al. JCI 2014	T cell acute lymphoblastic leukemia	Perphenazine	Compound E (Gamma secretase inhibitor)	Combination treatment leads to synergy only in GSI sensitive lines. Perphanazine also has single agent activity in GSI-resistant T-ALL lines Perphanazine causes regression in a zebrafish model of T-ALL. The effect is lost by overexpression of BCL2
Chien et al. Molecular Oncology 2015	Pancreatic cancer	Penfluridol, FTY720	Dasatinib	Phenothiazines identified in silico as class of molecules that can reverse dasatinib-resistance in pancreatic cancer cell lines Confirmed synergy with the structurally unrelated PP2A activator FTY720
Zonta et al. Blood 2015	Chronic lymphocytic leukemia	MP07-66 (FTY720 analog)	Dasatinib	Cell death induced by both dasatinib alone and combination treatment is reversible by okadaic acid Combination treatment increases dephosphorylation of AKT, GSK3b and SHP-1 over single agent
Richard et al. Oncotarget 2016	T cell acute lymphoblastic leukemia	OP449	Dovitinib (multikinase inhibitor)	Dovitinib identified in a screen for small molecules that synergize with OP449 in T-ALL cell lines Synergy observed in both NOTCH-dependent and NOTCH-independent lines
Smith et al. Oncotarget 2016	FLT3+ acute myeloid leukemia	FTY720 and related analog AAL(S)	Multiple FLT3 inhibitors	PP2A activity is reduced in primary AML cells and FLT3+ cell lines Both FTY720 and FLT3 inhibitors alone restore PP2A activity and in some cases the effect is additive
Shu et al. Nature 2016	Triple-negative breast cancer	Perphenazine (PPZ)	JQ1	Acquired resistance to JQ1 resulted from BRD4 hyperphosphorylation and increased association with MED1 leading to bromodomain independent binding of BRD4 to new super-enhancers PPZ treatment decreased BRD4 phosphorylation and restored sensitivity to JQ1
Martin et al. Breast Cancer Res 2017	Triple-negative breast cancer	FTY720	Gefitinib	Combination treatment enhanced tumor growth inhibition in 2 xenograft models 4T1 cells grown in immune-competent mice responded to combination treatment while no significant response was seen in 4T1 grown in nude mice
Kauko et al Sci Transl Med 2018	Non-small cell lung carcinoma	SMAP	AZD6244 (MEK inhibitor)	Reduced PP2A activity contributes to MEKi resistance due to enhanced mTOR signaling Combination treatment is significantly better than either agent, causing regression in 2 xenograft models of RAS-driven NSCLC
Hayashi et al Oncotarget 2018	ER+ breast cancer	Forskolin	Everolimus (mTORC1 inhibitor)	Sensitivity to EVE is correlated to the ability of EVE to decrease CIP2A levels CIP2A knockdown restores sensitivity to EVE in resistance clones