Abstract
Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically and pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response to EGFR blockade and identify alternative drug targets to overcome resistance. Both the tyrosine and global phosphoproteome as well as the proteome harbored distinctive response signatures. We found that increased pathway activity related to mitogen-activated protein kinase (MAPK) inhibition and abundant tyrosine phosphorylation of cell junction proteins, such as CXADR and CLDN1/3, in sensitive tumors, whereas epithelial-mesenchymal transition and increased MAPK and AKT signaling were more prevalent in resistant tumors. Furthermore, the ranking of kinase activities in single samples confirmed the driver activity of ERBB2, EGFR, and MET in cetuximab-resistant tumors. This analysis also revealed high kinase activity of several members of the Src and ephrin kinase family in 2 CRC PDX models with genomically unexplained resistance. Inhibition of these hyperactive kinases, alone or in combination with cetuximab, resulted in growth inhibition of ex vivo PDX-derived organoids and in vivo PDXs. Together, these findings highlight the potential value of phosphoproteomics to improve our understanding of anti-EGFR treatment and response prediction in mCRC and bring to the forefront alternative drug targets in cetuximab-resistant tumors.
| Original language | English |
|---|---|
| Article number | eabm3687 |
| Journal | Science Translational Medicine |
| Volume | 15 |
| Issue number | 709 |
| DOIs | |
| Publication status | Published - 16 Aug 2023 |
Bibliographical note
Funding Information:VitrOmics Healthcare Services (VHS), Cancer Center Amsterdam, and Netherlands Organisation for Scientific Research (NWO; Middelgroot project number 91116017) are acknowledged for support of the mass spectrometry infrastructure and Surfsara for computing infrastructure (reference e-infra180166). Furthermore, we thank both Cancer Center Amsterdam and René Vogels Stichting for providing a travel grant for R.B. and Dutch Cancer Society grant KWF 12516 for support of F.B. This work was funded by Dutch Cancer Society grant KWF 12516 (to C.R.J.); AIRC, Associazione Italiana per la Ricerca sul Cancro, Investigator Grants 20697 (to A.B.) and 22802 (to L.T.); AIRC 5x1000 grant 21091 (to A.B. and L.T.); AIRC/CRUK/FC AECC accelerator award 22795 (to L.T.); European Research Council Consolidator grant 724748 BEAT (to A.B.); H2020 grant agreement no. 754923 COLOSSUS (to L.T.); H2020 INFRAIA grant agreement no. 731105 EDIReX (to A.B.); and Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5x1000 Ministero della Salute 2016 (to L.T.).
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