Journal: Cancer discovery

Article Title: EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.

doi: 10.1158/2159-8290.CD-21-1168

Figure Lengend Snippet: Figure 2. High-throughput drug screen reveals cooperative induction of cell death by combined EGFR and FGFR inhibition in FGFR2 fusion+ ICC models. A. Schematic of high-throughput combination drug screen (Created with BioRender.com). The cell lines screened were: FGFR2-fusion+ ICC (ICC10/ICC10-6/ICC11/ICC13-7), FGFR2-fusion- ICC (ICC10-8/CCLP-1), FGFR2 amplified GC (KATO III/SNU-16). B. Screen results for the four FGFR2-fusion+ ICC cell lines tested. The chart shows the cooperative induction of cell death across the 111 drugs screened in combination with infigratinib 100 nM (upper panel), or futibatinib 40 nM (bottom panel), based on second highest single agent (HSA) score. Inhibitors of WT EGFR/ERBB signaling are highlighted red. The mutant selective EGFR inhibitor, CO1686 (Rociletinib) is highlighted black. Other inhibitors are color coded grey. C and D. Heat map and hierarchical cluster analysis generated in Morpheus (https://software.broadinstitute.org/morpheus/) based on second HSA score with infigratinib (C) and futibatinib (D) for cell death across all cell lines screened (color scheme is based on the minimum and maximum HSA values in each row). The top ranked combinations are presented as blown-up images on the right.

Article Snippet: IC50 values were determined by GraphPad Prism 9 using a 3-parameter dose-response model. Small molecule inhibitors were purchased from Selleckchem: infigratinib (S2183), futibatinib (S8848), pemigatinib (S0088), afatinib (S1011), gefitinib (S1025), EKB-569 (S1392).

Techniques: High Throughput Screening Assay, Inhibition, Amplification, Mutagenesis, Generated, Software