Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547

Description

Linghui Tan and five colleagues build an atlas of how cancers learn to resist a drug that blocks the FGFR receptor. The drug AZD4547 works until tumours rewire around it, by routes that vary by cancer. Their 2026 study merged two drug-response databases with single-cell gene data, covering 312 cell lines from eight cancer types. Machine learning models predicted sensitivity, and a synthetic-lethality screen looked for second targets whose loss would kill resistant cells.

Resistance wore many faces: a gene amplification in glioblastoma, marker shifts toward fat-burning metabolism and a mobile cell state elsewhere, and subpopulations present before treatment began. One bypass converged everywhere, though: resistant cells leaned on the related EGFR pathway and its downstream cascades. A prediction model scored 0.73 on held-out lines. In two FGFR-dependent cell models, hitting both receptors together killed more cells than either drug alone, confirming the screen's lead.

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Source: https://europepmc.org/article/MED/PMC13563855