The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Zhang Y., Chen J., She Y., Fang Z. et al. Cancer Cell. 44(1): p77-93.e8. (2026).
doi: 10.1016/j.ccell.2025.10.010.
doi: 10.1016/j.ccell.2025.10.010.
Summary of the findings
KRAS is a major oncogenic driver in colorectal cancer (CRC), with approximately 40% of CRC patients harboring KRAS mutations. Although dual KRAS and EGFR inhibition has shown clinical promise, most patients relapse within months due to acquired resistance. Notably, approximately one-third of resistant tumors lack genomic alterations, underscoring the importance of non-genetic adaptive mechanisms of therapeutic escape.
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Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, Zhang et al. discovered that CRC cells undergo lineage transition toward a Paneth cell-like state to survive dual KRAS-EGFR inhibition. Lineage tracing revealed Paneth-like cells arose from CRC cells via therapy-induced transdifferentiation, and targeted ablation of this population demonstrated that this transition directly contributes to therapeutic resistance. Through integrated CRISPR/Cas9 genetic screening and transcriptomic analysis, they identified SMAD1 as a key regulator of lineage plasticity that promote transdifferentiation through activation of FGFR3 pathway. FGFR3 signaling reactivates MAPK signaling in Paneth-like cells, thereby conferring resistance to KRAS-EGFR dual therapy. Consistent with this model, genetic or pharmacological inhibition of FGFR3 prevented the Paneth-like transition, restored sensitivity to KRAS-EGFR inhibition across multiple preclinical models.
Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, Zhang et al. discovered that CRC cells undergo lineage transition toward a Paneth cell-like state to survive dual KRAS-EGFR inhibition. Lineage tracing revealed Paneth-like cells arose from CRC cells via therapy-induced transdifferentiation, and targeted ablation of this population demonstrated that this transition directly contributes to therapeutic resistance. Through integrated CRISPR/Cas9 genetic screening and transcriptomic analysis, they identified SMAD1 as a key regulator of lineage plasticity that promote transdifferentiation through activation of FGFR3 pathway. FGFR3 signaling reactivates MAPK signaling in Paneth-like cells, thereby conferring resistance to KRAS-EGFR dual therapy. Consistent with this model, genetic or pharmacological inhibition of FGFR3 prevented the Paneth-like transition, restored sensitivity to KRAS-EGFR inhibition across multiple preclinical models.
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Future impact
The study establishes lineage plasticity as a key non-genetic mechanism by which KRAS-mutant CRC escapes dual KRAS-EGFR inhibition. More broadly, it expands the current framework of resistance beyond secondary genomic alterations and places therapy-induced cell-state transitions at the center of non-genetic resistance. By identifying FGFR3 as a critical effector of this program, the work provides a rationale for therapeutic strategies that co-target oncogenic signaling and lineage plasticity in KRAS-mutant CRC.
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