NPV-BEZ235PKI-587 GDC-0980PD0325901 Supplemental Figure S1 Structures of Inhibitors NVP-BEZ235; PKI-587; GDC-0980 and PD0325901.

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NPV-BEZ235PKI-587 GDC-0980PD Supplemental Figure S1 Structures of Inhibitors NVP-BEZ235; PKI-587; GDC-0980 and PD

pAKT Ser473 S6 - ERK AKT pAKT Thr308 Neurotensin + Insulin pS6 Ser240/244 pERK T202/Y204 NPV-BEZ235 μM Neurotensin + Insulin - pAKT Ser473 S6 ERK AKT pAKT Thr308 pS6 Ser240/244 pERK T202/Y204 Supplemental Figure S2 BA NPV-BEZ235 μM NPV-BEZ235 induces over-activation of ERK phosphorylation in MiaPaCa-2 (A) and PANC-1 (B) cells

NPV-BEZ235, µM PD Neurotensin+ Insulin ERK pERK T202/Y204 NPV-BEZ235 PD , µM Neurotensin+ Insulin Supplemental Figure S3 ERK pERK T202/Y A B The MEK inhibitor PD suppresses ERK over-activation induced by NPV-BEZ235 at nanomolar concentrations.

Supplemental Figure S4 BA pMEK Ser217/221 MEK Neurotensin+ Insulin NPV-BEZ 235,  M PD,  M CD pMEK Ser217/221 MEK Serum NPV-BEZ 235,  M PD,  M Overactivation of MEK phosphorylation by combination of dual PI3K/mTOR kinase inhibitor NPV- BEZ235 and MEK inhibitor PD

B Supplemental Figure S5 PKI GDC - - Neurotensin + Insulin BEZ Time, min Neurotensin + Insulin A Dual PI3K/mTOR kinase inhibitors NVP-BEZ235, PKI-587 and GDC-0980 suppress PIP 3 accumulation in PDAC cells in different times of stimulation.

IGF - + OSI-906 EGF Lapatinib - + EGF AG AG - + Lp - + OSI - + Fold increase by BEZ A D BC Supplemental Figure S6 NPV-BEZ235 enhances ERK pathway activation through a pathway that does not require EGFR, HER2 or insulin/IGF-1 receptor