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

2. pAKT Ser473 S6 - ERK AKT - 0.005.01.05.1.5 1 pAKT Thr308 Neurotensin + Insulin pS6 Ser240/244 pERK T202/Y204 NPV-BEZ235 μM Neurotensin + Insulin - pAKT Ser473 S6 ERK AKT - 0.005.01.05.1.5 1 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

3. NPV-BEZ235, µM - - 0.01 0.1 1 - - 0.01 0.1 1 PD 0325901 - - - - - + + + + + Neurotensin+ Insulin ERK pERK T202/Y204 NPV-BEZ235 PD0325901, µM - + + + + + - + + + + + Neurotensin+ Insulin Supplemental Figure S3 ERK pERK T202/Y204 - -.005.01.05.1 - -.005.01.05 0.1 A B The MEK inhibitor PD 0325901 suppresses ERK over-activation induced by NPV-BEZ235 at nanomolar concentrations.

4. Supplemental Figure S4 BA pMEK Ser217/221 MEK Neurotensin+ Insulin 1 - -.01.1 1 - 1 5 NPV-BEZ 235,  M PD,  M 1 - 1 5 1 CD pMEK Ser217/221 MEK Serum 1 - -.01.1 1 - 1 5 NPV-BEZ 235,  M PD,  M 1 - 1 5 1 Overactivation of MEK phosphorylation by combination of dual PI3K/mTOR kinase inhibitor NPV- BEZ235 and MEK inhibitor PD0325901.

5. B Supplemental Figure S5 PKI GDC - - Neurotensin + Insulin 0 15 30 60 - 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.

6. IGF - + OSI-906 EGF Lapatinib - + EGF AG-1478 - + 0 1 2 3 4 0.0 0.4 0.8 1.2 1.6 0.0 0.5 1.0 1.5 2.0 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