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Adaptive plasticity in targeted therapy

Vito Amodio1, Giorgio Patelli2, Alberto Bardelli3

  • 1IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.

Cancer Cell
|January 1, 2026
PubMed

Insights

Dual KRAS-EGFR inhibition in colorectal cancer triggers a reversible Paneth-like cell transition. This adaptive escape mechanism is sustained by a SMAD1-FGFR3 axis, reactivating mitogen-activated protein kinase (MAPK) signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Targeted therapies for colorectal cancer (CRC) often face adaptive resistance.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the adaptive response of colorectal cancer to dual KRAS-EGFR inhibition.
  • To elucidate the molecular mechanisms driving therapeutic escape.

Main Methods:

  • Utilized a dual KRAS-EGFR inhibition model in colorectal cancer.
  • Analyzed cellular transitions and signaling pathway reactivation.
  • Investigated the role of the SMAD1-FGFR3 axis in MAPK reactivation.

Main Results:

  • Dual KRAS-EGFR inhibition induced a reversible Paneth-like cell transition in CRC.
  • This transition sustained mitogen-activated protein kinase (MAPK) reactivation.
  • The SMAD1-FGFR3 axis was identified as a key mediator of MAPK reactivation.

Conclusions:

  • Lineage remodeling is an early adaptive escape mechanism from targeted therapy in CRC.
  • The findings highlight the clinical relevance of targeting KRAS and EGFR concurrently.
  • The SMAD1-FGFR3 axis represents a potential therapeutic target for overcoming resistance.

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