The abstract is read at the publisher; the summary is JClub's.
LCK transactivates EGFR in HuCCT1 cholangiocarcinoma cells, and pretreatment EGFR activity predicts afatinib response in 6 of 6 patient-derived xenograft models.
- Why it matters: EGFR inhibitors have failed in unselected cholangiocarcinoma, and LCK’s downstream effectors in CCA are unclear because canonical T-cell substrates are minimally expressed.
- What they did: Using unbiased proximity labeling in HuCCT1, the authors found EGFR in the LCK neighborhood; LCK depletion/inhibition lowered EGFR phosphorylation, and recombinant LCK increased EGFR phosphorylation in a cell-free assay. They then ranked 28 patient-derived xenografts by substrate-inferred EGFR activity and tested afatinib response, and applied an analogous activity score to primary tumors in two human CCA cohorts.
- The result: EGFR activity-based stratification correctly classified afatinib response in all six tested xenografts and stratified primary tumors in two cohorts, supporting EGFR activity as a functional biomarker for selecting CCA patients for EGFR-directed therapy.
The findingWhy it mattersWhat they didThe result
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