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Clinical target promiscuity: lessons from ras molecular trials

Ramesh Rengan1, Keith A Cengel, Stephen M Hahn

  • 1Department of Radiation Oncology, University of Pennsylvania, 2-Donner, HUP, 3400 Spruce Street, Philadelphia, PA 19104, USA.

Cancer Metastasis Reviews
|May 8, 2008
PubMed

Insights

Oncogenic Ras expression can cause tumor cells to resist radiation therapy. Prenyl transferase inhibitors (PTIs) can reverse this radioresistance, enhancing radiation

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Mutated Ras is implicated in ~30% of human tumors, with its dysregulation being critical in tumorigenesis.
  • Oncogenic Ras expression alters tumor cell radiosensitivity, impacting PI3K-dependent signaling.
  • Ras-mediated radioresistance presents a challenge in cancer treatment.

Purpose of the Study:

  • To review early data on oncogenic Ras expression affecting tumor cell radiosensitivity.
  • To discuss the role of prenyl transferase inhibitors (PTIs) in overcoming Ras-induced radioresistance.
  • To evaluate the predictive value of Ras biomarkers for clinical response to PTIs.

Main Methods:

  • Review of existing in vivo and in vitro studies on PTIs as radiosensitizers.
  • Analysis of mechanisms by which PTIs enhance radiation-induced cell kill.
  • Critical evaluation of Ras biomarkers in predicting clinical outcomes of PTI therapy.

Main Results:

  • Oncogenic Ras expression confers radioresistance, which can be reversed by PTIs.
  • PTIs demonstrate radiosensitizing effects in both in vitro and in vivo models.
  • Potential mechanisms for PTI-mediated radiosensitization involve enhancing radiation-induced cell kill.

Conclusions:

  • Ras-mediated radioresistance involves complex, interconnected pathways and a multifaceted genetic background.
  • A single Ras biomarker may be insufficient for predicting clinical response to PTIs.
  • Targeting PI3K-AKT signaling pathways represents a promising future strategy for clinical radiosensitization.

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