For these 28 selected genes (168 cross-talks), we observed the relative changes in GE values (parental vs resistant conditions) in their candidate signaling pathways. First we analyzed EGFR signaling pathway from Reactome and found that many of the constituent genes were up-regulated in one (or more) resistant conditions whereas in all of their corresponding parental conditions they were down-regulated (Additional file 1: Figure S1). These 168 selected cross-talks associated EGFR (or ErbB) signaling pathways with 6 other signaling pathways that were found in at least two different pathway analyses (i.e. Reactome and KEGG, or KEGG and WikiPathway, or Reactome and WikiPathway). In those 6 other signaling pathways, we also observed a similar phenomenon as above (Additional file 1: Figure S1). These 6 signaling pathways are Notch signaling (in Reactome, KEGG and WikiPathway), Wnt signaling (in Reactome, KEGG and WikiPathway), insulin receptor/IGF1R signaling (in Reactome and WikiPathway), GPCR signaling (in Reactome and WikiPathway), hedgehog (in KEGG and WikiPathway), and TGF- β receptor signaling (in Reactome and WikiPathway). Again, for many of the constituent genes of these 6 signaling pathways, expression was up-regulated in at least one of the resistant conditions whereas in all the corresponding parental conditions they were down-regulated. Primary findings regarding these 168 selected drug-resistant cross-talks are listed in Additional file 9: Table S8, and the top 50 of those 168 cross-talks (based on sorted Odds ratio) are shown in Table 2.
Table 2  Description of top 50 (based on sorted Odds ratio) cross-talks among all 168 potential drug-resistant cross-talks between EGFR/ErbB signaling and other pathways from all the analyses using Reactome, KEGG and WikiPathway databases in GSE38376
gene i ::gene j  EGFR/ErbB :: PrYijR=1 PrYijP=1  Odds ratio  Avg GEiP :  Avg GEiR :
Signaling pathway j  Avg GEjP  Avg GEjR
AKT2::MAML2 §,¶ Notch signaling 0.5 0.03 16.67 87.71::76.59 96.84::78.6
MDM2::APC §,$ Wnt signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76
KIT::CDC73 § Wnt signaling 0.5 0.03 16.67 82.14::104.01 82.68::110.88
MDM2::CDC73 § Wnt signaling 0.5 0.03 16.67 76.33::104.01 77.9::110.88
KIT::GNAQ § GPCR signaling 0.5 0.03 16.67 82.14::130 82.68::139.33
MDM2::GNAQ §,$ GPCR signaling 0.5 0.03 16.67 76.33::130 77.9::139.33
KIT::TSHR § GPCR signaling 0.5 0.03 16.67 82.14::71.32 82.68::71.66
MDM2::TSHR § GPCR signaling 0.5 0.03 16.67 76.33::71.32 77.9::71.66
AKT2::APC ¶ Wnt signaling 0.5 0.03 16.67 87.71::82.43 96.84::86.76
AKT2::APC ¶ Hippo signaling 0.5 0.03 16.67 87.71::82.43 96.84::86.76
AKT2::CDH1 ¶ Hippo signaling 0.5 0.03 16.67 87.71::74.2 96.84::79.8
AKT2::GNAQ ¶ Gnrh signaling 0.5 0.03 16.67 87.71::130 96.84::139.33
AKT2::GNAQ ¶ Calcium signaling 0.5 0.03 16.67 87.71::130 96.84::139.33
AKT2::MDM2 ¶ p53 signaling 0.5 0.03 16.67 87.71::76.33 96.84::77.9
MDM2::AKT2 $ Regulation of toll-like 0.5 0.03 16.67 76.33::87.71 77.9::96.84
receptor signaling
MDM2::AKT2 $ insulin signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84
MDM2::AKT2 $ RANKL/RANK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84
MDM2::AKT2 $ AMPK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84
MDM2::AKT2 $ MAPK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84
MDM2::AKT2 $ Tweak signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84
MDM2::AKT2 $ Toll-like 0.5 0.03 16.67 76.33::87.71 77.9::96.84
receptor signaling
MDM2::APC $ BDNF signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76
MDM2::APC $ Wnt signaling Netpath 0.5 0.03 16.67 76.33::82.43 77.9::86.76
MDM2::APC $ Wnt signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76
and Pluripotency
MDM2::COL1A1 $ Nanoparticle-mediated 0.5 0.03 16.67 76.33::91.44 77.9::102.54
activation of receptor
signaling
MDM2::COL1A1 $ Osteoblast signaling 0.5 0.03 16.67 76.33::91.44 77.9::102.54
MDM2::GNAQ $ TSH signaling 0.5 0.03 16.67 76.33::130 77.9::139.33
MDM2::GNAQ $ Serotonin Receptor 2 0.5 0.03 16.67 76.33::130 77.9::139.33
and STAT3 signaling
MDM2::GNAQ $ Serotonin Receptor 2 0.5 0.03 16.67 76.33::130 77.9::139.33
and ELK-SRF/GATA4
signaling
MDM2::ITK $ T-Cell Receptor and 0.5 0.03 16.67 76.33::89.86 77.9::93.27
Co-stimulatory signaling
MDM2::ITK $ Tcr signaling 0.5 0.03 16.67 76.33::89.86 77.9::93.27
MDM2::KIT $ Kit receptor signaling 0.5 0.03 16.67 76.33::82.14 77.9::82.68
MDM2::PAX5 $ ID signaling 0.5 0.03 16.67 76.33::68.91 77.9::71.02
MDM2::TSHR $ TSH signaling 0.5 0.03 16.67 76.33::71.32 77.9::71.66
AKT2::TP53 § Notch signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09
KIT::APC § Wnt signaling 0.5 0.04 12.5 82.14::82.43 82.68::86.76
KIT::MAML2 § Notch signaling 0.5 0.04 12.5 82.14::76.59 82.68::78.6
KIT::STK11 § IGF1R signaling 0.5 0.04 12.5 82.14::71.97 82.68::74.95
KIT::STK11 § insulin receptor signaling 0.5 0.04 12.5 82.14::71.97 82.68::74.95
KIT::TP53 § Notch signaling 0.5 0.04 12.5 82.14::128.73 82.68::155.09
MDM2::MAML2 §,$ Notch signaling 0.5 0.04 12.5 76.33::76.59 77.9::78.6
MDM2::STK11 § IGF1R signaling 0.5 0.04 12.5 76.33::71.97 77.9::74.95
MDM2::STK11 § insulin receptor signaling 0.5 0.04 12.5 76.33::71.97 77.9::74.95
MDM2::TP53 § Notch signaling 0.5 0.04 12.5 76.33::128.73 77.9::155.09
AKT2::GNAS ¶ Gnrh signaling 0.5 0.04 12.5 87.71::5465.46 96.84::6212.43
AKT2::GNAS ¶ Calcium signaling 0.5 0.04 12.5 87.71::5465.46 96.84::6212.43
AKT2::NF2 ¶ Hippo signaling 0.5 0.04 12.5 87.71::85.75 96.84::87.36
AKT2::TP53 ¶ P53 signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09
AKT2::TP53 ¶ Wnt signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09
CBL::CDH1 ¶ RAP1 signaling 0.5 0.04 12.5 194.46::74.2 208.45::79.8
Cross-talks found using signaling pathways from §Reactome, ¶KEGG, and $xx−xxWikiPathway Databases; Pathway j is the pathway containing gene j; PrYijR=1 and PrYijP=1 are the posterior probabilities of gene i:gene j in Resistant and Parental networks, respectively; AvgGEiP is the average GE value of all Parental conditions (each of which is an average of 3 samples) for gene i, AvgGEiR is similar but with Resistant conditions, and others are likewise similar.