Supplemental Fig. 1 DLD1 DKO1 Log2 ratio DKO3 Chromosome

Hec1A Hec1Aneo Log2 ratio Hec1Adelmut59 Chromosome

Hec1Adelmut124 Hec1AdelWT34 Log2 ratio Hec1AdelWT277 Chromosome

Supplemental Fig. 2 P-Akt P-ERK P-EGFR NRasGTP b-actin 10% FBS 0% FBS 0%FBS+EGF B A Mut/WT Mut/WT Mut/WT Mut/- -/WT Mut/- -/WT Mut/- -/WT P-Akt Mean fluorescent intensity P-ERK P-EGFR NRasGTP b-actin 0%FBS +EGF C 10% FBS 0% FBS 0%FBS+EGF D 10% FBS 0%FBS G12D/WT G12D/WT G12D/WT G12D/- WT/G13D WT/G13D WT/G13D G12D/- G12D/- -/WT -/WT WT/WT WT/WT WT/WT -/WT pY1125 pY1125 pY1069 pY1069 SW48 Tot-EGFR HCT116 Tot-EGFR pY774 pY774 Tot-Cbl Tot-Cbl

Supplemental Fig. 3 - - + + - - + + - - - - + + + + -/Mut WT/- -/Mut Conditioned media - - + + - - + + EGF - - - - + + + + pEGFR y1125 Hec1A b-actin P-EGFR y1125 DLD1 b-actin

Supplemental Fig. 4 Hec1A HCT116 ERK1/2 ERK1/2 AKT AKT WT/Mut - /Mut

Supplemental Fig. 5A DLD1 HCT116 % confluency Hec1A Time (hours) No siRNA NTC KRas HCT116 % confluency Hec1A Time (hours)

Supplemental Fig. 5B DLD1 % wound closure Hec1A Time (hours) No siRNA NTC siKRas No siRNA NTC KRas DLD1 % wound closure Hec1A 0 h Time (hours) 24 h

Supplemental Fig. 6

Supplemental Fig. 7 DUSP5 DUSP6 mutKRas WT KRas mutKRas WT KRas ETV1 Relative expression mutKRas WT KRas mutKRas WT KRas ETV1 ETV5 Relative expression ND ND mutKRas WT KRas mutKRas WT KRas

NT5E IER3 mutKRas WT KRas mutKRas WT KRas UPP1 mutKRas WT KRas Relative expression mutKRas WT KRas mutKRas WT KRas UPP1 Relative expression mutKRas WT KRas

Supplemental Fig. 8 A B C KRas NT5E (normalized to NTC) Expression ETV1 (normalized to NTC) Expression

Supplemental Fig. 8 1 1 1 D E p=0.0006 p=0.026 p=0.227 p=0.108 H838 1.2 p=0.18 1 1 1.2 H661 H1299 1.0 1.0 RKO HT55 0.8 0.8 H1568 Viability (Target gene:NTC) A427 Viability (Target gene:NTC) 0.6 0.6 A549 HupT3 0.4 0.4 H358 MiaPaca 0.2 0.2 KRas WT mut WT mut WT mut KRas WT mut WT mut WT mut siRNA KRas NT5E ETV1 siRNA KRas NT5E ETV1