Decoding intra-tumor heterogeneity towards understanding molecular mechanisms of resistance to anti-EGFR therapies

Background: Efforts have been made to develop therapies to target EGFR, a central proto-oncogene in the pathogenesis of cancer. However, the development of resistance is the major challenge of anti-EGFR therapy which is often mediated by intra- and inter- tumor heterogeneity. We wish to examine the relationship between intra-tumor heterogeneity and the development of resistance to EGFR inhibition in EGFR expressing cancers (Breast cancer and Glioblastoma).

Methods: We use bulk proteomics measurements and single cells analysis to determine the molecular basis of resistance to anti-EGFR therapy. Using thermodynamic-based surprisal analysis we identify an altered protein network in each malignancy. The altered network can be composed of several distinct subnetworks. Using single-cell analysis we examine further whether those subnetworks are located in the same cells or in different subpopulations. This understanding will help us to accurately design combinations of targeted drugs.

Results: The analysis revealed that resistance to anti-EGFR therapies occurred when the altered protein network was composed of several independent subnetworks, in which EGFR was not necessarily involved. Thus EGFR inhibition influenced only partially the altered protein network thereby leaving some of the subnetworks active in the tumor cells.

Conclusion: These results provide us with the hypothesis that identification of the entire set of the altered subnetworks in each tumor or cellular subpopulations in which EGFR is not involved is crucial to inhibit the entire signaling flux and prevent the clonal expansion that mediates resistance to anti-EGFR therapy.