Supplementary Figure 1 100 B. 50.

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Supplementary Figure 1 100 B. 50

Supplementary Figure 2 Supplementary Figure 3 Cell Viability, % RPMI8226 100 100 Cell Viability, % 50 Cell Viability, % 50 Bortezomib, nM 0 250 500 1000 2000 Metformin, µM 100 100 U266 Cell Viability, % 50 Cell Viability, % 50 Bortezomib, nM 100 SP RPMI8226 U266 0 250 500 1000 2000 Metformin, µM Colony Formation, % 50 0 250 500 1000 2000 Metformin, µM

Supplementary Figure 4 100 RPMI8226 Colony Formation, % 50 0 250 500 1000 2000 Metformin, µM 100 U266

Supplementary Figure 5 Supplementary Figure 6 Cell Viability, % No Addition Chloroquine Hydroxychloroquine Bafilomycin A1 No Drug Bortezomib 5nM Metformin 500µM Bortezomib 5nM + Metformin 500µM 100 100 Cell Viability, % Cell Viability, % 50 50 Drug Treatment 0 1 3 Bortezomib, nM

Supplementary Figure 7

PARP Supplementary Figure 8 SP MP SP MP Bortezomib Metformin PI3K-p85 PI3K-p110 β- Actin P -Ser473-AKT β- Actin Total AKT P -AKT/AKT Bortezomib - - + + - - + + Metformin - + - + - + - + SP MP Bortezomib - - + + - - + + Metformin - + - + - + - + PARP Cleaved PARP β-Tubulin

Supplementary Figure 14 Supplementary Figure 9 Untreated 22 Metformin BTZ BTZ + Metformin 22 Mean Body Weight, grams 20 18 0 8 16 Days from Start of Treatment

Supplementary Figure 10 Supplementary Figure 14 Untreated 22 Metformin BTZ BTZ + Metformin 22 Mean Body Weight, grams 20 18 0 8 16 Days from Start of Treatment

Annexin-positive cells (%) Supplementary Figure 11 Supplementary Figure 12 70 AMPK-WT AMPK-a1/a2 KO shRNA Control HSPA5 60 120 100 80 60 40 20 50 Cell Viability, % 40 Annexin-positive cells (%) 30 20 10 0 3 5 10 20 BTZ (5nM) - + - + - + Metformin (500µM) - - + + - - Phenformin (25µM) - - - - + + Bortezomib, nM

Patient #3 Patient #1 Patient #2 Patient #4 Patient #5 Patient #6 Supplementary Figure 13 BTZ BTZ + Metformin (500µM) 100 Patient #3 Patient #1 100 Patient #2 100 Cell Viability, % Cell Viability, % Cell Viability, % 50 50 50 0 5 10 20 0 5 10 20 0 5 10 20 Bortezomib, nM Bortezomib, nM Bortezomib, nM Patient #4 Patient #5 Patient #6 100 100 100 Cell Viability, % Cell Viability, % Cell Viability, % 50 50 50 0 5 10 20 0 5 10 20 0 5 10 20 Bortezomib, nM Bortezomib, nM Bortezomib, nM

Supplementary Figure 14 Untreated 22 Metformin BTZ BTZ + Metformin 22 Mean Body Weight, grams 20 18 0 8 16 Days from Start of Treatment