Supplementary Table S1: List of validated hits from N minus RAS screen Entrez Gene S.N. Gene ID 1 Methyl CpG Binding Protein 2 (MECP2) 4204 2 Orthodenticle Homeobox 2 (OTX2) 5015 3 Target Of Myb1 (Chicken) (TOM1) 10043 4 G Protein-Coupled Receptor 171 (GPR171) 29909 5 Flotillin 2 (FLOT2) 2319 6 Chromosome 12 Open Reading Frame 74 (C12ORF74) 338809 7 Histone Cluster 1, H2bn (HIST1H2BN) 8341 8 Histone Cluster 1, H3f (HIST1H3F) 8968 9 Solute Carrier Family 25, Member 41 (SLC25A41) 284427 10 Chimerin 1 (CHN1) 1123 11 Zinc Finger Protein 658 (ZNF658) 26149 12 Lipoxygenase Homology Domains 1 (LOXHD1) 125336 13 Regulator Of G-Protein Signaling 3 (RGS3) 5998 14 Chloride Channel, Voltage-Sensitive Kb (CLCNKB) 1188 15 Calmodulin 3 (Phosphorylase Kinase, Delta) (CALM3) 808 Supplementary Table S2: Amplicons in Human Cancer (from Broad Institute TCGA Copy Number Portal) #Genes Residual Q- High- Peak Region in Peak value Overall Focal level chr7:55065906-55102668 1 0 0.382 0.068 0.084 chr8:128739771-128769210 1 1.74E-272 0.453 0.129 0.139 chr11:69460105-69484581 2 2.12E-222 0.208 0.106 0.065 chr17:37855834-37875909 1 1.22E-204 0.199 0.054 0.038 chr19:30306820-30315735 1 5.49E-183 0.24 0.066 0.055 chr12:69212831-69260428 2 1.07E-144 0.211 0.053 0.04 chr3:169416569-169490229 2 2.03E-124 0.335 0.118 0.093 chr12:58135796-58155222 6 3.76E-122 0.205 0.045 0.033 chr11:70140426-70213455 1 5.18E-118 0.204 0.102 0.062 chr1:150519259-150703005 8 3.65E-113 0.37 0.1 0.078 chr3:181256573-181731927 3 9.82E-81 0.328 0.118 0.089 chr11:77613200-77640847 1 1.45E-78 0.169 0.068 0.031 chr8:38171486-38254058 2 2.04E-71 0.234 0.067 0.057 chr5:1288615-1299329 1 1.40E-60 0.317 0.071 0.076 chr4:55008314-55104469 1 1.46E-51 0.114 0.05 0.023 chr12:25344325-25370603 3 2.82E-44 0.245 0.041 0.047 chr8:41761807-41929152 1 4.94E-41 0.259 0.06 0.055 chr15:99056932-99774542 6 2.14E-37 0.145 0.064 0.018 chr1:204353015-204538342 3 1.58E-36 0.363 0.046 0.066 chr12:889902-1041097 12 9.28E-34 0.247 0.058 0.043 chr20:30203029-30315025 2 9.01E-33 0.391 0.045 0.073 chr1:40377907-40416849 0 7.80E-29 0.145 0.051 0.018 chr1:242980673-247812431 84 1.22E-28 0.352 0.072 0.06 chr19:39770395-39892270 9 1.27E-28 0.217 0.043 0.035 chr17:57922442-57943519 1 1.34E-27 0.242 0.048 0.029 chrX:153016891-153342426 18 1.21E-26 0.176 0.059 0.018 (MECP2 containing amplicon) chr7:92173409-92556768 4 8.22E-26 0.363 0.039 0.05 chr1:160989893-161115583 9 2.07E-25 0.369 0.077 0.069 chr8:101324125-101642253 4 9.37E-25 0.417 0.061 0.104 chr20:52156927-52364760 2 3.87E-24 0.401 0.043 0.083 chr8:37492872-37529770 0 1.51E-23 0.223 0.059 0.051 chr6:43638636-43987936 5 1.62E-21 0.197 0.043 0.027 chr3:197077908-197335218 1 2.59E-21 0.315 0.112 0.078 chr13:113757997-114302622 13 1.20E-19 0.179 0.058 0.03 chr11:102266643-102488711 3 1.99E-19 0.134 0.035 0.019 chr17:27148617-27422161 14 1.97E-18 0.185 0.048 0.018 chr20:62187416-62219648 39 1.61E-17 0.397 0.056 0.079 chr19:15338573-15408584 2 1.95E-17 0.194 0.04 0.028 chr14:36544027-37264674 9 2.45E-15 0.144 0.043 0.019 chr6:20396454-20522290 1 1.01E-14 0.205 0.037 0.029 chr8:144939389-145147978 12 1.55E-14 0.424 0.105 0.108 chr9:35654478-35737197 10 1.99E-13 0.138 0.044 0.019 chr11:66980818-67054144 3 2.88E-13 0.176 0.072 0.022 chr4:1778801-1816690 2 2.44E-12 0.107 0.042 0.016 chr18:20358314-20503269 1 1.35E-11 0.143 0.036 0.022 chr17:73466243-73637996 8 6.82E-11 0.258 0.07 0.027 chr6:107198296-107289865 2 1.13E-09 0.105 0.024 0.015 chr11:34639284-34838823 1 1.69E-09 0.127 0.033 0.014 chr10:76501637-77227430 10 2.01E-09 0.107 0.035 0.013 chr2:178085599-178160931 4 1.47E-08 0.163 0.043 0.013 chr8:80714469-81835247 5 3.48E-08 0.385 0.041 0.082 chr17:77765982-77821663 3 5.70E-07 0.256 0.072 0.024 chr5:37909815-44676519 52 5.95E-07 0.288 0.038 0.061 chr4:73903374-74158212 2 1.78E-06 0.095 0.039 0.014 chr14:105197567-105318962 7 2.49E-06 0.14 0.045 0.013 chr22:18613737-22139416 90 3.08E-06 0.14 0.038 0.014 chr19:55547934-58878226 147 5.70E-06 0.192 0.045 0.017 chr8:55091227-55382067 1 8.28E-06 0.349 0.045 0.067 chr6:64084316-64402884 2 1.45E-05 0.153 0.038 0.015 chr12:66217394-66241372 2 1.58E-05 0.197 0.037 0.026 chr5:176445948-176904216 15 1.60E-05 0.166 0.052 0.015 chr9:4894234-5591850 8 2.00E-05 0.126 0.03 0.019 chr19:35494834-36225620 37 4.83E-05 0.229 0.047 0.035 chr14:20501368-21697941 66 7.10E-05 0.144 0.049 0.014 chr19:10238547-10877387 28 2.28E-04 0.176 0.034 0.021 chr7:146690968-158383607 112 5.87E-04 0.339 0.045 0.04 chr17:48773492-49002559 7 9.47E-04 0.218 0.031 0.02 chr10:5507029-5769453 4 0.003 0.167 0.037 0.022 chr13:73907772-73972011 0 0.00339 0.156 0.031 0.029 chr7:708774-1243749 22 0.00349 0.375 0.046 0.045 chr6:11203906-11588708 2 0.00387 0.203 0.043 0.026 chr2:60243955-63176269 21 0.0124 0.193 0.031 0.014 chr3:13669693-13758663 2 0.0347 0.115 0.033 0.01 chr8:115442722-118152629 9 0.0752 0.43 0.083 0.109 chr9:139822542-140366608 44 0.0981 0.143 0.043 0.011 chr2:113962850-114139862 2 0.102 0.16 0.034 0.011 chr10:123172835-123398895 1 0.117 0.096 0.029 0.009 chr13:27260341-28888798 23 0.146 0.135 0.031 0.023 chr7:116314195-116508848 2 0.156 0.346 0.027 0.041 Note: Q values (False Discovery Values) below 0.25 are considered significant Supplementary Table S3: Cancer cell lines used in current study with their MECP2 expression and RAS/MAPK/PI3K pathways mutation status (based on COSMIC, canSAR, ATCC, and CCLE databases) RAS Other relevant mutations Cell lines mutation (in MAPK and PI3K pathways) BREAST MECP2 overexpressing cell lines: BT549 Wild-type PTENV275X MDAMB468 Wild-type PTENA72fsX5 MDAMB453 Wild-type PTENE307K; PIK3CAH1047R BT20 Wild-type PIK3CAP539R; PIK3CAH1047R MCF7 Wild-type PIK3CAE545K Cell lines with low MECP2: ZR75-1 Wild-type PTENL108R MDAMB231 KRASG13D BRAFG464V; NF2E231* T47D Wild-type PIK3CAH1047R HCC38 Wild-type LUNG MECP2 overexpressing cell lines: NCI-H1755 Wild-type BRAFG468A NCI-H23 KRASG12C NCI-H1993 Wild-type MET amplification NCI-H2228 Wild-type EML4-ALK fusion NCI-H2170 Wild-type NCI-H2009 KRASG12A NCI-H522 Wild-type NCI-H1563 Wild-type Cell lines with low MECP2: NCI-H1437 Wild-type NCI-H1395 Wild-type BRAFG469A NCI-H838 Wild-type NCI-H2347 NRASQ61R OVARIAN MECP2 overexpressing cell lines: EFO21 Wild-type IGROV1 Wild-type PTENY155C; PIK3CAR38C; AKT2V198A SKOV3 Wild-type ERBB2 amplification; PIK3CAH1047R CAOV3 Wild-type PTENW274G OVCAR4 Wild-type Cell lines with low MECP2: OVCAR3 Wild-type CCNE1 amplification; AKT2 amplification OVCAR5 KRASG12V OVCAR8 KRASP121H ERBB2G776V .