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Analysis of Individual Protein Regions Provides Novel Insights on Cancer Pharmacogenomics

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Analysis at the functional region level allows us to gain novel insights from pharmacogenomics data.

(a, b) Mapping of the different ERBB3 functions to specific regions of the protein. Each functional relationship can be associated to a specific domain or intrinsically disordered region in ERBB3. For example, EGF receptor domains (red boxes in (b)) mediate physical interactions between ERBB3 and EGFR and NRG1 (red edges in (a)). (c) Methods focusing at the whole-protein level can not find any association between ERBB3 mutations and the activity of PF2341066. (d) Mutations altering specifically the N-terminal EGF receptor are associated to lower drug activity. (e) Mutations affecting another PFR in ERBB3, its kinase domain, and that, thus, are mainly affecting other functional regions, are not associated to any changes in drug activity. (f), Venn diagram showing the different thresholds that we have established in order to minimize false positives. We only kept PFRs with (I) p<0.001 when compared to cell lines with no mutation in the protein, (II) p<0.05 when compared to cell lines with mutations in other regions of the same protein and (III) with p>0.01 at the protein level.

Figure 1