PMC:4307189 / 42224-44220 JSONTXT

{"project":"2_test","denotations":[{"id":"25599599-19754359-14868164","span":{"begin":221,"end":223},"obj":"19754359"},{"id":"25599599-22423264-14868164","span":{"begin":221,"end":223},"obj":"22423264"},{"id":"25599599-23950876-14868164","span":{"begin":221,"end":223},"obj":"23950876"},{"id":"25599599-19153117-14868165","span":{"begin":413,"end":415},"obj":"19153117"},{"id":"25599599-19754359-14868166","span":{"begin":574,"end":576},"obj":"19754359"},{"id":"25599599-19754359-14868167","span":{"begin":723,"end":725},"obj":"19754359"},{"id":"25599599-17902048-14868168","span":{"begin":927,"end":929},"obj":"17902048"},{"id":"25599599-16037379-14868169","span":{"begin":1115,"end":1117},"obj":"16037379"},{"id":"25599599-23542173-14868170","span":{"begin":1825,"end":1826},"obj":"23542173"},{"id":"25599599-16452501-14868171","span":{"begin":1992,"end":1994},"obj":"16452501"}],"text":"Several studies have reported extensive cross-talk between IR (insulin receptor)/IGF1R (insulin-like growth factor-1 receptor) and EGFR/ErbB signaling pathways contributing to acquired drug resistance in various cancers [62-64]. Loduvini et al. reported significant correlation between worse disease-free survival and high co-expression of both EGFR/ErbB and IGF1R in NSCLC (non-small-cell lung cancer) patients [65]. EGFR/ErbB can physically interact with other non-ErbB family receptors at the cell surface and can form heterodimers with receptors like IGF1R, PDGFR etc. [62]. Moreover, the EGFR/ErbB and IGF1R pathways can also cross-talk indirectly via physical interactions between their downstream shared-components [62]. It has been reported recently that gefitinib (an EGFR TKI) inhibits the phosphorylation of IRS1 by IR, but also triggers the association between IRS1 and IGF1R which in turn induces drug-resistance [66]. Knowlden et al. showed the cross-talk between IGF1R and EGFR signaling pathways occurred in tamoxifen-resistant MCF7 and T47D breast cancer cell-lines but not in non-resistant cells [18]. Our findings suggest KIT:STK11 (in Reactome), MDM2:STK11 (in Reactome), MDM2:AKT2 (in WikiPathway), MYC:AKT2 (in WikiPathway), TP53:AKT2 (in WikiPathway), MDM2:CBL (in WikiPathway), MDM2:SOCS1 (in WikiPathway), and TP53:SOCS1 (in WikiPathway) as putative drug-resistant cross-talks between the IGF1R/IR and EGFR/ErbB signaling pathways. For the MDM2 and STK11 (also known as LKB1) genes, which we identified as a putative cross-talk between EGFR and IGF1R signaling, we did not find any direct supporting evidence in the literature. However, this association is plausible in the resistant conditions given that Yamaguchi et al. suggested EGFR signaling may cross-talk with the AMPK/LKB signaling pathway [1]. Moreover, Levine et al. reported interconnections between p53 and IGF1R/AKT/mTOR pathways where both LKB1 and MDM2 participate in a series of pathway cross-talks [67]."}