Analysis of Individual Protein Regions Provides Novel Insights on Cancer Pharmacogenomics
(a) Missense mutations in PIK3CA can have opposite effects in terms of AEW541 activity depending on the PFR affected. Mutations in the p85-binding and PIK accessory domains are associated with lower and higher drug activities respectively (upper panel). By integrating our analysis with proteomics data from TCPA we have been able to propose a mechanism for that. It appears that IRS1 protein expression is lower in cells with p85-binding mutations, but higher in those with PIK mutations (second panel). Moreover, Akt1 phosphorylation levels are higher in cell lines with p85-binding domain mutations (two lower panels). (b) Proposed mechanisms for the two PFR-AEW541 associations. AEW541 inhibits the kinase domain of IGF1R (upper blue protein). In those cell lines with mutations in the PIK domain of PIK3CA (shown in blue PIK3CA's structure), there is a gain of interaction between this protein and IRS1 (I). This will likely increase the signaling through IGF1R (II), explaining why cell lines with mutations in this domain are more sensitive to the inhibition of this receptor. On the other hand, cell lines with mutations in the p85-binding domain (shown in red in PIK3CA's structure) have lower IRS1 expression and higher AKT1 phosphorylation levels. Together, this suggests that PIK3CA is active in this cell lines independently of its interaction with extracellular receptors, signaling directly downstream towards AKT1 (III). This would explain why these cells are resistant to AEW541.