RESEARCH POSTER PRESENTATION DESIGN © 2015

www.PosterPresentations.com

• Alterations in KRAS, BRAF and EGFR as well as pan-Ras classifier score (data not shown)strongly predict high expression of the adenosine fingerprint in pan-cancer TCGA.

• In KRAS, BRAF and EGFR wild-type patients, high CD73 expression is significantly associatedwith poor prognosis. High CD73 expression is strongly associated with poor prognosis in EGFRand KRAS mutant patients, and good prognosis in BRAF mutant patients.

• Adenosine fingerprint exhibits higher expression in KRAS mutant versus wild-type in CRC andNSCLC patients as well as cell lines at the gene and protein level.

• EGFR mutant NSCLC patients have significantly poor prognosis associated with lower rate ofdurable clinical benefit with pembrolizumab treatment (data not shown).

• High expression of adenosine fingerprint and PD1 in T cells is associated with resistance to anti-PD1 therapy in mutant KRAS and EGFR murine NSCLC.

Udyavar AR, DiRenzo D, Piovesan D, Ashok D, Anderson AE, Young SW, Walters MJ, Tan JBL Arcus Biosciences, Inc. 3928 Point Eden Way, Hayward, CA 94545 (USA)

Altered pan-Ras pathway and activating mutations in EGFR result in elevated CD73 in multiple cancers

• AB928, a dual A2aR/A2bR antagonist, andAB680, a potent selective inhibitor of CD73, canrescue the immunosuppressive effects ofadenosine in experimental cell culture andtumor models.

• Oncogene-driven cancers tend to be non-responsive to PD(L)-1 inhibition.

• Here we show that pan-RAS, BRAF and EGFRalterations drive the expression of CD73, whichmay contribute to suppressed anti-tumorimmunity.

• Regression analysis: We used linear models adjusted for individual tumor types to assess if theexpression of CD73 and other genes in the adenosine fingerprint can be predicted by alterations in299 consensus cancer driver genes (Bailey et.al Cell (2018)) in pan-cancer TCGA dataset (GDCCommons). For regression models, multiple testing correction was performed using Benjamini-Hochberg method.

• Survival analysis: Kaplan-Meier curves were plotted in R showing log-rank p-values. Cox-regression analysis were used to compute hazard ratios and p-values.

• Histology: CD73 (Cell Signaling, D7F9A) immuno-histochemistry (IHC) was performed onsections of formalin fixed paraffin embedded (FFPE) tumor tissue and quantified using QuPathsoftware.

• Cancer cell lines: RNAseq data was obtained from Broad’s Cancer Cell Line Encyclopedia(CCLE) database. RNA from human cancer cell lines was extracted and converted into cDNA.Real-time qPCR was performed using Taqman probes. HPRT1 was used as the housekeepinggene and raw data was analyzed using the 2-ΔCT method. CD73, CD39 and CD26 proteinexpression on human cancer cell lines was determined using flow cytometry.

Introduction

KRAS, BRAF and EGFR strongly predict adenosine fingerprint expression in pan-cancer TCGA

Results

Materials and Methods

Conclusions

Interested in a career at Arcus? Visit www.arcusbio.com

AACR 2019 National Meeting; Atlanta Abstract # 2526

Figure 1. (A) CD73 and TNAP expression was derived from pan-cancer TCGA dataset. Numbers onY-axis indicate ratio of log2 CPM values for CD73 and TNAP. Tumors on left are high in CD73 andlow in TNAP whereas tumors on right are high in TNAP and low in CD73. (B) Linear model estimatesadjusted for tumor type of alterations in cancer driver genes that predict CD73 expression. (C) X-axisdenotes the positive (left) and negative (right) regulators of CD73 from panel B. Y-axis shows linearmodel estimates adjusted for tumor type for each gene in the adenosine fingerprint. Stars indicatesignificant FDR (*** < 0.001,** <0.01,* < 0.2).

CD73 expression is prognostic in KRAS, BRAF and EGFR mutant patients in pan-cancer TCGA

Figure 2. (A) shows frequency and type of alterations in KRAS, BRAF and EGFR from cBioPortal.Inset shows number of mutations in a given gene. (B) Kaplan-Meier curves show impact of CD73expression on the individual cancer drivers with wild-type and altered status on overall survival.High protein expression of CD73 in KRAS mutated patients compared

to wild-type in CRC and NSCLC

Figure 4. (A) Heatmap of adenosine fingerprint in Broad’s CCLE RNAseq data for representativeCRC and NSCLC cell lines. (B) Correlation scatterplot of CD73 expression in cancer cell lines frompanel A and qPCR. (C) Flow cytometry proteomic validation of CD73, CD39 and CD26 expression inKRAS WT and ALT CRC and NSCLC cell lines.

High expression of adenosine fingerprint in KRAS altered versus wild-type in CRC and NSCLC cell lines

Figure 3. (A) Representative CD73 IHC images for KRAS wild-type and altered NSCLC and CRCpatients. (B) Quantification of percent CD73 positive area in CRC and NSCLC patients.

High expression of adenosine fingerprint and PD1 in T cells correlates with resistance to anti-PD1 in KRAS and EGFR mutant NSCLC

Figure 5. Left to right – RNAseq gene expression (dataset from Koyama et.al Nat. Comm. (2015)) ofCD73 (Nt5e), CD39 (Entpd1), A2aR (Adora2a) and PD1 (Pdcd1) in T cells derived from either EGFRL858R/T790M mutant or KRAS G12D mutant mouse tumors that were either untreated (Untrt) orresistant to anti-PD1 (aPD1-R). P-values denote significance by Wilcoxon ranked-sum test.

A

0.0

2.5

5.0

7.5

10.0

WT ALT

KRAS alterations

% C

D73

pos

itive

sta

inin

g

N=9 N=13

KRAS alterationsBWT ALT

NSCLC

CRC

A

p = 0.23

n=3 n=5

p = 0.037

n=5 n=54

5

6

CD39 expression in T-cells

�

p = 0.14

n=3 n=5

�

�

�

p = 0.4

n=5 n=5

EGFRmut KRASmut

Untrt aPD1-R

7.0

7.5

8.0

8.5

Log2

CPM

CD73 expression in T-cells

p = 0.14

n=3 n=5

�

�

p = 0.037

n=5 n=54.5

5.0

5.5

6.0

A2aR expression in T-cells

p = 0.037

n=3 n=5

�

p = 0.022

n=5 n=5

6

7

8

9

PD1 expression in Tcells

Untrt aPD1-RUntrt aPD1-R Untrt aPD1-R Untrt aPD1-R Untrt aPD1-R Untrt aPD1-R Untrt aPD1-R

EGFRmut KRASmut EGFRmut KRASmut EGFRmut KRASmut

CD73 CD39 A2aR PD1

Log2

CPM

Alte

ratio

n Fr

eque

ncy

10%

20%

30%

40%

50%

GBM LUADESCAHNSCLGG STADLUSCSKCMUCSBLCACESCSARCCOADACC HCCBRCACHOLOV READPAADKIRPPRADTGCTPCPG KIRCKICHMESOTHCAUCECUVM

Mutation Fusion Amplification Deep Deletion

A289V/T/D

Recep_L_domain Furin-like Recep_.. GF_recep.. Pkinase_Tyr

0 1210aa200 400 600 800 1000

0

35

# EG

FR M

utat

ions

Alte

ratio

n Fr

eque

ncy

10%

20%

30%

40%

50%

60%

PAADCOADREADLUADUCSUCECSTADTGCTOV ESCABLCACHOLCESCLUSCSARCSKCMLGG MESOHCCBRCAGBM KIRPHNSCPRADACCTHCAKIRCKICHPCPG UVM

Mutation Fusion AmplificationDeep Deletion

G12D/V/C and 4 more

Ras

0 189aa100

0

560

# KR

AS M

utat

ions

Alte

ratio

n Fr

eque

ncy

10%

20%

30%

40%

50%

60%

THCASKCMCOADOV LUADUCSBLCALUSCSTADSARCREADUCECGBM PRADCHOLESCAPAADHNSCACC LGG KIRPBRCAMESOPCPG CESCKIRCHCCKICHTGCTUVM

Mutation Fusion Amplification Deep Deletion Multiple Alterations

V600E/M/G and 2 more

RBD C1_1 Pkinase_Tyr

0 766aa200 400 600

0

589

# BR

AF M

utat

ions

G598V/A/E L858R

BRAF

KRAS

EGFR

A2aR

A2aR

A2aRA2bR

ATP AMP Adenosine

CD39 CD73

NK Cells

T cells

DC, TAM, MDSC

PI3Kγ

PI3Kδ

PI3Kγ/δ

IPI-549

AB928

AB928

AB928

AB680

CD38 CD203a

NAD+ ADPR

Mutation

Alteration type

Fusion

Amplification

Deep deletion

Multiple alterations

KRAS EGFRBRAFB+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

++++++++++++++ ++++++ +

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

++++++++++++ + + +++

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + +

++ +

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++ ++++ + + + +++

p < 0.0001

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25Time (years)

Ove

rall

Surv

ival

(OS)

++++

KRAS:ALT; CD73:HighKRAS:ALT; CD73:LowKRAS:WT; CD73:HighKRAS:WT; CD73:Low ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++++++ + + +

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++

+++ + ++ ++

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ +

++ +

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++ ++ + +++

p < 0.0001

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25

++++

BRAF:ALT; CD73:HighBRAF:ALT; CD73:LowBRAF:WT; CD73:HighBRAF:WT; CD73:Low ++++++++++++++

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++ ++

+

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

++++++++++++++++

++++++ ++ +

+ +

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +

++ +

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p < 0.0001

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25

++++

EGFR:ALT; CD73:HighEGFR:ALT; CD73:LowEGFR:WT; CD73:HighEGFR:WT; CD73:Low

Time (years) Time (years)

IsotypeStain

H651 (WT)

CD39

CD73

H441 (ALT)

CD26

H1395 (WT)

H650 (ALT)

NSCLC

SKCO1 (ALT)

RKO (WT)

SW1116 (ALT)

CRCC

A B

●

●●NCI−H1395

NCI−H1651

NCI−H441

NCI−H650

RKO

SKCO1

SW1116

0.0

2.5

5.0

7.5

2 4 6 8CD73 (CCLE RNAseq)

CD

73 (q

tPC

R)

Tissue● CRC

NSCLC

Mutation●●

ALTWT

●

●●NCI−H1395

NCI−H1651

NCI−H441

NCI−H650

RKO

SKCO1

SW1116

0.0

2.5

5.0

7.5

2 4 6 8CD73 (CCLE RNAseq)

CD

73 (q

tPC

R)

Tissue● CRC

NSCLC

Mutation●●ALTWT●

●●NCI−H1395

NCI−H1651

NCI−H441

NCI−H650

RKO

SKCO1

SW1116

0.0

2.5

5.0

7.5

2 4 6 8CD73 (CCLE RNAseq)

CD

73 (q

tPC

R)

Tissue● CRC

NSCLC

Mutation●●ALTWT

CCLE RNAseq

Aden

osin

e pa

thw

ay g

enes

CD39

CD73

ADA

CD26

ADORA1

ADORA2A

ADORA2B

ADORA3

NCI−H1395

RKO

NCI−H1651

SKCO

1

SW11

16

NCI−H441

NCI−H650

KRAS_StatusTissue

Z−score

−2−10123

KRAS StatusALTWT

TissueNSCLCCRC

CCLE RNAseq

Aden

osin

e pa

thw

ay g

enes

CD39

CD73

ADA

CD26

ADORA1

ADORA2A

ADORA2B

ADORA3

NCI−H1395

RKO

NCI−H1651

SKCO

1

SW11

16

NCI−H441

NCI−H650

KRAS_StatusTissue

Z−score

−2−10123

KRAS StatusALTWT

TissueNSCLCCRC

CCLE RNAseq

Aden

osin

e pa

thw

ay g

enes

CD39

CD73

ADA

CD26

ADORA1

ADORA2A

ADORA2B

ADORA3

NCI−H1395

RKO

NCI−H1651

SKCO

1

SW11

16

NCI−H441

NCI−H650

KRAS_StatusTissue

Z−score

−2−10123

KRAS StatusALTWT

TissueNSCLCCRC

CCLE RNAseq

Aden

osin

e pa

thw

ay g

enes

CD39

CD73

ADA

CD26

ADORA1

ADORA2A

ADORA2B

ADORA3

NCI−H1

395

RKO

NCI−H1

651

SKCO

1

SW11

16

NCI−H4

41

NCI−H6

50

KRAS_StatusTissue

Z−score

−2−10123

KRAS StatusALTWT

TissueNSCLCCRCA1R

A2AR

A2BR

A3R

CD73

/TNA

P (L

og2)

ratio

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CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26A1R

A2aRA2bR

KRASBRAF

METFUBP1

RAC1EGFR

CDK4CTCF

PGRRET

RASA1JA

K1PHF6

NF1CIC

ARID1AZFHX3

ZCCHC12

GNA11

SMAD4

USP9X

CDKN2AFA

T1

PIK3R1

SCAF4PMS2

RNF43

SMC1ABCOR

FGFR2

COL5A1ATMKMT2B

CTNNB1MYC

RAD21PTEN

Positive regulators of CD73

Aden

osin

e pa

thw

ay g

enes

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CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26

RHOB

TBL1XR1

KEAP1

ZFP36L2

FGFR3

FOXA1FLT

3

TRAF3

RNF111

PPP2R1ATXNIP

STAG2

RIT1TGIF1

FOXQ1ATR

CYSLTR2

PCBP1

PIK3R2

ASXL1

HIST1H1CKLF5

PIK3CBSPOP

MECOM

CACNA1A

CTNND1

DACH1XPO1

ZNF750

FBXW7MUC6

KDM6AGATA

3

ZBTB20

PIK3CARB1SOX17

SMARCA4KITCHD8

CHD4APOB

Negative regulators of CD73

Increased expression in Mutants

−0.50

0.00

Model estimates0.25

Decreased expression in Mutants

A1RA2aRA2bR

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CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26A1R

A2aRA2bR

KRASBRAF

METFUBP1

RAC1EGFR

CDK4CTCF

PGRRET

RASA1JA

K1PHF6

NF1CIC

ARID1AZFHX3

ZCCHC12

GNA11

SMAD4

USP9X

CDKN2AFA

T1

PIK3R1

SCAF4PMS2

RNF43

SMC1ABCOR

FGFR2

COL5A1ATMKMT2B

CTNNB1MYC

RAD21PTEN

Positive regulators of CD73

Aden

osin

e pa

thw

ay g

enes

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CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26

RHOB

TBL1XR1

KEAP1

ZFP36L2

FGFR3

FOXA1FLT

3

TRAF3

RNF111

PPP2R1ATXNIP

STAG2

RIT1TGIF1

FOXQ1ATR

CYSLTR2

PCBP1

PIK3R2

ASXL1

HIST1H1CKLF5

PIK3CBSPOP

MECOM

CACNA1A

CTNND1

DACH1XPO1

ZNF750

FBXW7MUC6

KDM6AGATA

3

ZBTB20

PIK3CARB1SOX17

SMARCA4KITCHD8

CHD4APOB

Negative regulators of CD73

Increased expression in Mutants

−0.50

0.00

Model estimates0.25

Decreased expression in Mutants

A1RA2aRA2bR

A B

C

CD73 higher in Altered vs WT

CD73 lower in Altered vs WT

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*

**

**

**

***

******

***

*

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*

*

******

*

*

****

*

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*

**

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**

*

***

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***

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**

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***

**

*

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*

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*

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*

*

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****

**

****

CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26A1R

A2aRA2bR

KRASBRAF

METFUBP1

RAC1EGFR

CDK4CTCF

PGRRET

RASA1JA

K1PHF6

NF1CIC

ARID1AZFHX3

ZCCHC12

GNA11

SMAD4

USP9X

CDKN2AFA

T1

PIK3R1

SCAF4PMS2

RNF43

SMC1ABCOR

FGFR2

COL5A1ATMKMT2B

CTNNB1MYC

RAD21PTEN

Positive regulators of CD73

Aden

osin

e pa

thw

ay g

enes

*

*

*

***

*

*

**

***

*

*

*

*

**

*

**

***

*

*

*

*

**

****

**

*

*

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**

***

*

***

*

*

*****

**

*

********

*

*

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**

**

*

***

***

***

*

****

*

****

***

***

*****

*

**

*

*

*****

**

*

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*

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*

*

*

***

**

*

*

**

**

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*

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**

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***

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* ***

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**

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*

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*

CD73CD39CD38

ENPP1CD73/TNAP

TNAPADA

CD26A1R

A2aRA2bR

RHOB

TBL1XR1

KEAP1

ZFP36L2

FGFR3

FOXA1FLT

3

TRAF3

RNF111

PPP2R1ATXNIP

STAG2

RIT1TGIF1

FOXQ1ATR

CYSLTR2

PCBP1

PIK3R2

ASXL1

HIST1H1CKLF5

PIK3CBSPOP

MECOM

CACNA1A

CTNND1

DACH1XPO1

ZNF750

FBXW7MUC6

KDM6AGATA

3

ZBTB20

PIK3CARB1SOX17

SMARCA4KITCHD8

CHD4APOB

Negative regulators of CD73

Increased expression in Mutants

−0.50

0.00

Model estimates0.25

Decreased expression in Mutants

Positive regulators of CD73 expression Negative regulators of CD73 expression

Oncogenic drivers of CD73 expression

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n=63

5n=

502n=

161n=

375n=

178n=

177n=

155n=

259n=

500n=

86n=

288n=

36n=

103n=

171n=

411n=

511n=

304n=

371n=

80n=

528n=

498n=

257n=

524n=

141n=

65n=

534n=

501n=

547n=

56n=

374n=

79n=

150

**** * ** **** ****

****

****

****

****

****

**** *** ****

****** ****

****

****

****** *****

****

****

****

****

−10

−5

0

5

10

CRCTHCA

ESCASTA

DPCPG

PAAD

GBMSARC

HNSCMESO

KIRPCHOL

SKCM

HER2+ BRCA

BLCALGG

CESCLIHC

UVM

ER/PR+ BRCA

PRADBRCA

LUAD

TNBC BRCAKICH

KIRCLUSC

UCECUCS OV

ACCTGCT

log2

ratio

(CD7

3/TN

AP)

4 8CD73 (log2 CPM) TNAP (log2 CPM) ● ● ●0 4 8

CD73 vs TNAP

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n=63

5n=

502n=

161n=

375n=

178n=

177n=

155n=

259n=

500n=

86n=

288n=

36n=

103n=

171n=

411n=

511n=

304n=

371n=

80n=

528n=

498n=

257n=

524n=

141n=

65n=

534n=

501n=

547n=

56n=

374n=

79n=

150

**** * ** **** ****

****

****

****

****

****

**** *** ****

****** ****

****

****

****** *****

****

****

****

****

−10

−5

0

5

10

CRCTHCA

ESCASTA

DPCPG

PAAD

GBMSARC

HNSCMESO

KIRPCHOL

SKCM

HER2+ BRCA

BLCALGG

CESCLIHC

UVM

ER/PR+ BRCA

PRADBRCA

LUAD

TNBC BRCAKICH

KIRCLUSC

UCECUCS OV

ACCTGCT

log2

ratio

(CD7

3/TN

AP)

4 8CD73 (log2 CPM) TNAP (log2 CPM) ● ● ●0 4 8

CD73 vs TNAP

CD73 (log2 CPM)

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n=63

5n=

502n=

161n=

375n=

178n=

177n=

155n=

259n=

500n=

86n=

288n=

36n=

103n=

171n=

411n=

511n=

304n=

371n=

80n=

528n=

498n=

257n=

524n=

141n=

65n=

534n=

501n=

547n=

56n=

374n=

79n=

150

**** * ** **** ****

****

****

****

****

****

**** *** ****

****** ****

****

****

****** *****

****

****

****

****

−10

−5

0

5

10

CRCTHCA

ESCASTA

DPCPG

PAAD

GBMSARC

HNSCMESO

KIRPCHOL

SKCM

HER2+ BRCA

BLCALGG

CESCLIHC

UVM

ER/PR+ BRCA

PRADBRCA

LUAD

TNBC BRCAKICH

KIRCLUSC

UCECUCS OV

ACCTGCT

log2

ratio

(CD7

3/TN

AP)

4 8CD73 (log2 CPM) TNAP (log2 CPM) ● ● ●0 4 8

CD73 vs TNAP

TNAP (log2 CPM)

CD73/TNAP ratio

-log 1

0FD

R

CD73

/TNA

P (lo

g 2ra

tio)