Network organization of the 19,940 DTP drug and compound activities in CellMiner identify clusters
Vinodh Rajapakse, 2013
Network organization of the compounds (V. Rajapakse)
Growth inhibition 50%, total
protein (at 48 hours by
sulforhodamine B assay):
Cell lines are variable in their pharmacological response to the 19,940 compounds in toto, identifying an indices of cellular robustness
WC Reinhold et al, PLOS One, 2014
Applications of the molecular pharmacological data and tools:
Four transcript expression examples
Identification of genes with correlated expression that also function together in epithelial-like tumor cells
Gene Expression Correlations in Human Cancer Cell Lines Define Molecular Interaction Networks for Epithelial
Phenotype. Kohn, et al.. PLoSONE, Jan. 2014.
Gmeiner WH, Reinhold WC, Pommier Y, Mol Cancer Ther, 2010.
* * * *
Identification of the SLFN11 gene using the activities of five drugs (FdUMP(10), fluorouracil, floxuridine, topotecan, and irinotectan)
When Schlafen-11 (SLFN11) expression is high, the drug works better.
Demonstration of SLFN11 expression as a dominant, causal molecular event for activity fluctuations for DNA damaging drugs
Broad correlations to 4 clinically important classes of drugs, topoisomerase1 and 2 inhibitors, alkylating agents and DNA synthesis inhibitors
-2 -1 0 1 2
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 C O:HCT_116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UAC C_257 ME:UAC C_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NC I_H226 LC:NC I_H23 LC:NCI_H322M LC:NC I_H460 LC:NC I_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NC I_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
Transcript intensity (Z scores) SLFN11 average Z scores
Pattern comparison SLFN11 transcript
levels
✓
Zoppoli et al, PNAS, Aug. 2012.
Ipilimumab is a FDA approved (in 2011) drug for un-resectable and metastatic melanoma
CTLA4 expression and the drug Ipilimumab
William Reinhold, Yves Pommier
It inhibits CTLA4 (cytotoxic T-lymphocyte-associated protein 4) in T- lymphocytes, allowing them to recognize and destroy cancer cells (Funt, Oncology, 2014).
CTLA4 is not known to be expressed in melanoma.
We find CTLA4 is expressed at the transcript level in a melanoma specific manner.
WC Reinhold et al, Clinical Can Res, 2015
Cunningham et al, PNAS, Aug. 2012
RUNX1 and CBFB expression identification of the HIV TAT antagonist Ro5-3335 as a candidate core binding factor (CBF) leukemia treatment
Cunningham et al showed causal linkage between the Ro5-3335 and the genes.
1. Ro5-3335 Interacts with RUNX1 and CBFβ directly.
2. Ro5-3335 repress RUNX1/CBFB-dependent transactivation in reporter assays.
3. Ro5-3335 repress RUNX1-dependent hematopoiesis in zebrafish.
4. Ro5-3335 preferentially kills human CBF leukemia cell lines.
5. Ro5-3335 rescued the AML preleukemic phenotype in RUNX1–ETO transgenic zebrafish.
6. Ro5-3335 reduced leukemia burden in a mouse CBFB–MYH11 leukemia model.
Identified Ro5-3335 (NSC743504) as a candidate treatment.
Pattern comparison RUNX1 and CBFB expression
-3 -2 -1 0 1 2
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
Transcript intensity (Z scores) CBFB average Z scores
-2 -1 0 1 2 3
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D C NS:SF_268 C NS:SF_295 C NS:SF_539 C NS:SNB_19 C NS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
Transcript intensity (Z scores) RUNX1 average Z scores
CBFB RUNX1
A systems pharmacological application of the data
Triple negative breast cancer
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
BR:MDA_MB_231
B R :M C F 7
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
BR:HS578T
B R :M C F 7
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
−6 −4 −2 0 2 4 6
−6
−4
−2 0 2 4 6
Es tr o ge n r e ce p to r p o si t ve
Scatter plot of 20,002 compound activities (GI50s) in 2 divergent forms of breast cancer
Omic survey of the pharmacological data for triple negative breast cancer identified a non-cancer bone-density drug (zometa) with superior activity as
compared to all FDA-approved and clinical trial cancer drugs.
Compounds
FDA-approved breast cancer drugs Zometa (NSC 721517)
FDApproved drugs used in breast cancer:
capecitabine, carboplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, mitomycin, mitoxantrone, paclitaxel, and vincristine.
Robert and Reinhold, Bulletin du Cancer, 2015
Molecular Data integration
3 forms of molecular data in 3 genes identify RAS activation in 27/60 of the NCI-60
-2 -1 0 1 2 3
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_ 3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
HRAS
-2 -1 0 1 2 3 4
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_ 549 BR:T47D CNS:SF_ 268 CNS:SF_ 295 CNS:SF_ 539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE :CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE :RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_ 62 LC:HOP_ 92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_ 393 RE:SN12C RE:TK_ 10 RE:UO_31
KRAS
-2 -1 0 1 2 3
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_ 19 CNS:SNB_ 75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_ 10 RE:UO_31
NRAS
*
* *
*
*
* *
*
* *
* *
* *
*
* *
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:E KVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_ 3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
HRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE :CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_ 257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
KRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE :CCRF_ CEM LE :HL_60 LE :K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_ 3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
NRAS
Activation of RAS by three molecular mechanisms
DNA amplification RNA transcript expression Activating mutations
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_ 549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE :RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_ 10 RE:UO_31
HRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_ 15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_ 2 ME:SK_MEL_28 ME:SK_MEL_ 5 ME:UACC_257 ME:UACC_ 62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_ 3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_ 1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
KRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_ 549 BR:T47D CNS:SF_ 268 CNS:SF_ 295 CNS:SF_ 539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE :HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE :SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_ 3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_ 393 RE:SN12C RE:TK_10 RE:UO_31
NRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_ CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_ 3 OV:OVCAR_ 4 OV:OVCAR_ 5 OV:OVCAR_ 8 OV:SK_ OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
HRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_ 3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_ 10 RE:UO_31
KRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
NRAS
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE :MO LT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_ 3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
All RAS
By gene
Composite RAS activation patterns Total
.
.
Reinhold et al., Clinical Can Res, 2015
3 forms of molecular data predict PTEN knockdown in 8/60 cell lines, and demonstrate its association to drug activity.
Reinhold et al., Clinical Can Res, 2015
0 20 40 60 80 100
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_ 268 CNS:SF_ 295 CNS:SF_ 539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_ 4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_ MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_ MB_ 435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_ 393 RE:SN12C RE:TK_10 RE:UO_31
Summation of variants - 4 . 0 -3 .0 - 2 . 0 -1 .0 0 . 0 1 . 0 2 .0
B R : M C F 7 B R : M D A _ M B _ 2 3 1 B R : H S 5 7 8 T B R : B T _ 5 4 9 B R : T 4 7 D C N S : S F _ 2 6 8 C N S : S F _ 2 9 5 C N S : S F _ 5 3 9 C N S : S N B _ 1 9 C N S : S N B _ 7 5 C N S : U 2 5 1 C O : C O L O 2 0 5 C O : H C C _ 2 9 9 8 C O : H C T _ 1 1 6 C O : H C T _ 1 5 C O : H T 2 9 C O : K M 1 2 C O : S W _ 6 2 0 L E : C C R F _ C E M L E : H L _ 6 0 L E : K _ 5 6 2 L E : M O L T _ 4 L E : R P M I_ 8 2 2 6 L E : S R M E : L O X IM V I M E : M A L M E _ 3 M M E : M 1 4 M E : S K _ M E L _ 2 M E : S K _ M E L _ 2 8 M E : S K _ M E L _ 5 M E : U A C C _ 2 5 7 M E : U A C C _ 6 2 M E : M D A _ M B _ 4 3 5 M E : M D A _ N L C : A 5 4 9 L C : E K V X L C : H O P _ 6 2 L C : H O P _ 9 2 L C : N C I_ H 2 2 6 L C : N C I_ H 2 3 L C : N C I_ H 3 2 2 M L C : N C I_ H 4 6 0 L C : N C I_ H 5 2 2 O V : IG R O V 1 O V : O V C A R _ 3 O V : O V C A R _ 4 O V : O V C A R _ 5 O V : O V C A R _ 8 O V : S K _ O V _ 3 O V : N C I_ A D R _ R E S P R : P C _ 3 P R : D U _ 1 4 5 R E : 7 8 6 _ 0 R E : A 4 9 8 R E : A C H N R E : C A K I_ 1 R E : R X F _ 3 9 3 R E : S N 1 2 C R E : T K _ 1 0 R E : U O _ 3 1
T ra n s c r ip t i n te n s i t y (Z s c o r e s )
-2.0 -1.5 -1.0 -0.5 0.0 0.5
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_ 2998 CO:HCT_ 116 CO:HCT_15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_ 62 ME:MDA_MB_ 435 ME:MDA_N LC:A549 LC:EKVX LC:HOP_ 62 LC:HOP_ 92 LC:NCI_H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_H460 LC:NCI_H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_ 31
DNA Copy number
Genetic variants PTEN knockdowns Transcript z scores
aCGH
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*
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*
*
* *
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*
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Composite pattern
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Pattern comparison
*
An significant enrichment for PTEN- associated drugs (p < 0.01).
0 1
BR:MCF7 BR:MDA_MB_231 BR:HS578T BR:BT_549 BR:T47D CNS:SF_268 CNS:SF_295 CNS:SF_539 CNS:SNB_19 CNS:SNB_75 CNS:U251 CO:COLO205 CO:HCC_2998 CO:HCT_ 116 CO:HCT_ 15 CO:HT29 CO:KM12 CO:SW_620 LE:CCRF_CEM LE:HL_ 60 LE:K_562 LE:MOLT_4 LE:RPMI_8226 LE:SR ME:LOXIMVI ME:MALME_3M ME:M14 ME:SK_MEL_2 ME:SK_MEL_28 ME:SK_MEL_5 ME:UACC_257 ME:UACC_62 ME:MDA_MB_435 ME:MDA_ N LC:A549 LC:EKVX LC:HOP_62 LC:HOP_92 LC:NCI_ H226 LC:NCI_H23 LC:NCI_H322M LC:NCI_ H460 LC:NCI_ H522 OV:IGROV1 OV:OVCAR_3 OV:OVCAR_4 OV:OVCAR_5 OV:OVCAR_8 OV:SK_OV_3 OV:NCI_ADR_RES PR:PC_3 PR:DU_145 RE:786_0 RE:A498 RE:ACHN RE:CAKI_ 1 RE:RXF_393 RE:SN12C RE:TK_10 RE:UO_31
Knockdown Composite
