Prediction of signaling cross-talks contributing to acquired drug resistance in breast cancer cells by Bayesian statistical modeling.

BACKGROUND

Initial success of inhibitors targeting oncogenes is often followed by tumor relapse due to acquired resistance. In addition to mutations in targeted oncogenes, signaling cross-talks among pathways play a vital role in such drug inefficacy. These include activation of compensatory pathways and altered activities of key effectors in other cell survival and growth-associated pathways.

RESULTS

We propose a computational framework using Bayesian modeling to systematically characterize potential cross-talks among breast cancer signaling pathways. We employed a fully Bayesian approach known as the p 1-model to infer posterior probabilities of gene-pairs in networks derived from the gene expression datasets of ErbB2-positive breast cancer cell-lines (parental, lapatinib-sensitive cell-line SKBR3 and the lapatinib-resistant cell-line SKBR3-R, derived from SKBR3). Using this computational framework, we searched for cross-talks between EGFR/ErbB and other signaling pathways from Reactome, KEGG and WikiPathway databases that contribute to lapatinib resistance. We identified 104, 188 and 299 gene-pairs as putative drug-resistant cross-talks, respectively, each comprised of a gene in the EGFR/ErbB signaling pathway and a gene from another signaling pathway, that appear to be interacting in resistant cells but not in parental cells. In 168 of these (distinct) gene-pairs, both of the interacting partners are up-regulated in resistant conditions relative to parental conditions. These gene-pairs are prime candidates for novel cross-talks contributing to lapatinib resistance. They associate EGFR/ErbB signaling with six other signaling pathways: Notch, Wnt, GPCR, hedgehog, insulin receptor/IGF1R and TGF- β receptor signaling. We conducted a literature survey to validate these cross-talks, and found evidence supporting a role for many of them in contributing to drug resistance. We also analyzed an independent study of lapatinib resistance in the BT474 breast cancer cell-line and found the same signaling pathways making cross-talks with the EGFR/ErbB signaling pathway as in the primary dataset.

CONCLUSIONS

Our results indicate that the activation of compensatory pathways can potentially cause up-regulation of EGFR/ErbB pathway genes (counteracting the inhibiting effect of lapatinib) via signaling cross-talk. Thus, the up-regulated members of these compensatory pathways along with the members of the EGFR/ErbB signaling pathway are interesting as potential targets for designing novel anti-cancer therapeutics.