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Cancer Cells Expressing Oncogenic Rat Sarcoma Show Drug-Addiction Toward Epidermal Growth Factor Receptor Antibodies

Joseph Tintelnot1, Sina Metz1, Marie Trentmann1

  • 1Department of Oncology and Hematology, BMT With Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Frontiers in Oncology
|February 11, 2020
PubMed

Insights

Epidermal growth factor receptor (EGFR) antibodies paradoxically stimulate proliferation in RAS-mutant colorectal cancer by prolonging MAPK signaling. This suggests drug holidays to prevent resistance and clear RAS-mutant subclones.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) antibodies can be detrimental in metastatic colorectal cancer (mCRC) with oncogenic Rat sarcoma (RAS) mutations.
  • RAS-mediated resistance to EGFR-directed therapy is a significant clinical challenge, necessitating understanding of underlying mechanisms.

Purpose of the Study:

  • To investigate the molecular mechanisms by which EGFR antibodies promote tumor growth in RAS-mutant mCRC.
  • To explore potential therapeutic strategies to overcome or prevent RAS-mediated resistance to EGFR inhibitors.

Main Methods:

  • Utilized a Ba/F3 cellular model engineered for EGFR/RAS dependency to study proliferation, RAS activity, and MAPK signaling.
  • Administered therapeutic EGFR antibodies (cetuximab, panitumumab) and antibody-chemotherapy combinations.
  • Monitored cellular responses upon antibody withdrawal to assess drug-addiction phenotypes.

Main Results:

  • EGFR antibodies cetuximab and panitumumab induced paradoxical proliferation in cells with oncogenic RAS (KRAS G12V).
  • This stimulatory effect resulted from prolonged mitogen-activated protein-kinase (MAPK) signaling due to antibody-EGFR interaction.
  • RAS mutant cells exhibited growth retardation after antibody withdrawal, indicating a drug-addiction phenotype.

Conclusions:

  • EGFR antibodies can paradoxically sustain MAPK signaling downstream of oncogenic RAS, driving proliferation in RAS-mutant tumors.
  • The observed drug-addiction phenotype supports the use of fixed-duration therapy or liquid-biopsy-guided drug holidays to prevent RAS-mutant subclone selection.
Keywords:
EGFR antibodiesMAPK signalingacquired resistancecolorectal canceroncogenic RAS

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