Luc Friboulet

Tyrosine kinase inhibitors (TKIs) have transformed oncogene-driven cancer treatment, but durable responses remain limited by residual disease and acquired resistance. Drug-tolerant persister (DTP) cells represent one therapy-surviving component of minimal residual disease (MRD). This Review examines experimental and computational strategies, including patient-derived xenografts, CRISPR screens, single-cell, spatial, multi-omic and artificial intelligence approaches, to define DTP states, MRD heterogeneity, microenvironmental interactions and clinically actionable vulnerabilities with greater resolution in TKI-treated cancers.

Hallmarks from gene set enrichment analysis (GSEA) of bulk RNA sequencing from tissue biopsies of FGFR inhibitor-naïve patients.

Clinical and molecular characteristics of FGFR inhibitor-naïve patients experiencing acquired resistance to lirafugratinib with off-target alterations only.

Clinical and molecular evolution of patient ST2726.

Supplementary Figure S1. Chemistry/X-ray. Supplementary Figure S2. Biochemical activity of ALK TKIs. Supplementary Figure S3. Kinome profiling of NVL-655. Supplementary Figure S4. Potency in cell viability assay. Supplementary Figure S5. Maximal effect (Emax) in cell viability assay. Supplementary Figure S6. Cellular activity of NVL-655. Supplementary Figure S7. Comparing NVL-655 and lorlatinib potency. Supplementary Figure S8. Pathway analysis in cell lines. Supplementary Figure S9. Further evidence for on-target activity of NVL-655. Supplementary Figure S10. TRK activity. Supplementary Figure S11. Selectivity for ALK versus TRK using additional assays. Supplementary Figure S12. In vivo studies for ALK fusion with a wild-type kinase domain. Supplementary Figure S13. In vivo studies for ALK fusion with G1202R or I1171N single mutations. Supplementary Figure S14. In vivo studies for ALK fusion with G1202R compound mutations. Supplementary Figure S15. Pharmacodynamic analysis in G1202R compound mutation models. Supplementary Figure S16. Body weight and H&E staining for the YU-1077 intracranial study. Supplementary Figure S17. Estimating TRKB inhibition in humans and mice.

Primary resistance to lirafugratinib in FGFR inhibitor-naïve patients.

Differential impact on intracellular signaling exerted by lirafugratinib and futibatinib in FGFR2::BICC1 Ba/F3 with a kinase domain with no mutations (wild-type, WT), and with M538I or L618F mutations.

In vivo evaluation of lirafugratinib and futibatinib in ST4193 PDX.

Clinical and molecular evolution of patients pretreated with a FGFR inhibitor before undergoing lirafugratinib.