In order to interrogate the contribution of EGFR to downstream signaling under ALK inhibition, we conducted phosphoproteomics for two ALK-driven cell lines, DFCI032 and H3122, using the ALK inhibitor crizotinib or in combination with the EGFR inhibitor gefitinib. Kinase-Substrate Enrichment Analysis (KSEA) and Phosphoproteomics Dissection Using Networks (PHOTON) analysis were used to identify whether a signaling node was functionally regulated based on substrate phosphorylation or on protein-protein interaction partner phosphorylation, respectively. Strikingly, both methods showed that EGFR was functionally downregulated by ALK inhibition. ALK was also considered functionally more downregulated under EGFR/ALK dual inhibition compared to ALK inhibition alone by KSEA analysis. These data suggest ALK and EGFR engage in overlapping signaling pathways. Collectively, EGFR and ALK dual inhibition can significantly delay or prevent the emergence of ALK TKI resistance by suppressing critical overlapping signaling pathways and promotes signaling reprogramming in cancer cells. READ ARTICLE
AACR abstract DOI: 10.1158/1538-7445.AM2020-1865
Authors: Nan Chen, Anh T. Le, Andrea E. Doak, Guolin Zhang, Bin Fang, Eric B. Haura and Robert C. Doebele