We found MDM2:APC (in Reactome and WikiPathway), KIT:CDC73 (in Reactome), MDM2:CDC73 (in Reactome), CBL:APC (in Reactome and KEGG), PDGFRA:APC (in Reactome), and CBL:CDC73 (in Reactome), AKT2:APC (in KEGG), AKT2:TP53 (in KEGG), and TP53:APC (in WikiPathway) as putative drug-resistant cross-talks between EGFR/ErbB and Wnt signaling pathways. Deregulation of the Wnt/ β-catenin signaling pathway plays a critical role in various cancers including breast, colorectal, pancreatic and colon cancer [47,48], and its association with drug-resistance has been studied by several research groups [47-50]. Recently, it has been reported that resistant cell lines exhibited increased Wnt signaling in both breast and colon cancer [49,50]. Loh et al. showed that genes in the Wnt signaling pathway, in both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and the independent arms (ROR2, JUN), were up-regulated in cell lines resistant to tamoxifen compared to the parental MCF7 cell line [49]. Furthermore, ROR1, a constituent gene of Wnt signaling pathway, plays a sustainer role in EGFR-mediated prosurvival signaling in lung adenocarcinoma via signaling cross-talk and was therefore reported to be a potential therapeutic target [51]. APC and MDM2 in the MDM2:APC cross-talk are both tumor suppressors; they co-regulate DNA polymerase- β [52,53] which is reported to be hyper-activated in a cis-diamminedichloroplatinum(II) resistant P388 murine leukemia cell line [54]. Again, β-catenin whose stability is negatively regulated by APC [55], confers resistance to PI3K/Akt inhibitors in colon cancer [56].