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Constitutively active Harvey Ras confers resistance to epidermal growth factor receptor-targeted therapy with

Rodney B Luwor1, Yang Lu, Xinqun Li

  • 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.

Cancer Letters
|March 18, 2011
PubMed

Insights

Harvey Ras (H-Ras) mutations can cause resistance to epidermal growth factor receptor (EGFR) targeted therapies, similar to Kirsten Ras (K-Ras) mutations. Constitutively active H-Ras confers resistance to EGFR inhibitors like cetuximab and gefitinib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Kirsten Ras (K-Ras) mutations are known predictors of resistance to epidermal growth factor receptor (EGFR) targeted therapies.
  • The role of Harvey Ras (H-Ras) mutations in conferring resistance to anti-EGFR therapy remains less understood.

Purpose of the Study:

  • To investigate whether Harvey Ras (H-Ras) mutations can also confer resistance to EGFR-targeted therapy.
  • To determine the impact of constitutively active H-Ras on cellular signaling pathways and anti-tumor effects in response to EGFR inhibitors.

Main Methods:

  • Expression of constitutively active H-Ras (Ras G12V) in A431 human vulvar squamous carcinoma cells.
  • Assessment of cellular resistance to EGFR inhibitors cetuximab and gefitinib.
  • Evaluation of downstream signaling pathways including Akt and Erk phosphorylation.
  • Analysis of Hypoxia-Inducible Factor 1-alpha (HIF-1α) expression and transcriptional activity.
  • In vitro and in vivo studies to assess anti-tumor effects.

Main Results:

  • A431 cells expressing constitutively active H-Ras exhibited marked resistance to cetuximab and gefitinib.
  • EGFR inhibition of Akt and Erk phosphorylation was reduced in H-Ras mutated cells.
  • H-Ras expression diminished the inhibition of HIF-1α expression and transcriptional activity by EGFR inhibitors.
  • Anti-tumor effects of EGFR inhibitors were reduced both in vitro and in vivo in the presence of active H-Ras.

Conclusions:

  • Constitutively active Harvey Ras (H-Ras) can confer resistance to anti-EGFR therapy in cancer cells.
  • H-Ras mutations represent a potential mechanism of resistance to EGFR-targeted treatments, similar to K-Ras mutations.
  • These findings highlight the importance of evaluating H-Ras mutation status in predicting response to EGFR inhibitors.

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