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Primary Prevention and Interception Studies in RAS-Mutated Tumor Models Employing Small Molecules or Vaccines

Konstantin H Dragnev1, Ronald A Lubet2, Mark Steven Miller2

  • 1Dartmouth Cancer Center, Lebanon, New Hampshire.

Cancer Prevention Research (Philadelphia, Pa.)
|July 19, 2023
PubMed

Insights

Targeting RAS-mutated cancers is challenging, but prevention and interception are promising. Various agents, including glucocorticoids, RXR agonists, and COX inhibitors, effectively prevent or intercept RAS-mutated tumors across different organs.

Area of Science:

  • Oncology
  • Cancer Prevention
  • Molecular Biology

Background:

  • Therapeutic targeting of RAS-mutated cancers remains difficult.
  • Prevention and interception strategies (treatment before or during preinvasive stages) show preclinical promise.
  • RAS pathway mutations are common drivers in various human cancers.

Purpose of the Study:

  • To evaluate the efficacy of various agents in preventing or intercepting RAS-mutated tumors across different organs.
  • To explore non-RAS-specific agents for their potential in cancer prevention and interception.
  • To investigate combination therapies for enhanced prevention of RAS-driven cancers.

Main Methods:

  • Utilized preclinical cancer models, including A/J mouse lung, rat azoxymethane-induced colon, and N-nitroso-N-methylurea-induced rat breast models.
  • Administered various agents such as glucocorticoids, retinoid X receptor (RXR) agonists, cyclooxygenase (COX) 1/2 inhibitors, EGFR inhibitors, and selective estrogen receptor modulators.
  • Assessed tumor development and response to treatment in KRAS-mutated, HRAS-mutated, and wild-type tumor contexts.

Main Results:

  • Glucocorticoids and RXR agonists were effective in preventing/intercepting KRAS-mutated lung tumors, irrespective of specific mutations.
  • COX 1/2 inhibitors and difluoromethylornithine showed efficacy in preventing/intercepting both KRAS-mutated and wild-type colon tumors.
  • Combination therapy with COX and EGFR inhibitors nearly eliminated pancreatic tumors in transgenic mice.
  • Selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists were effective in HRAS-mutated breast tumors, while tipifarnib preferentially inhibited HRAS-mutant tumors.

Conclusions:

  • Many agents not directly targeting the RAS pathway demonstrate organ-specific efficacy in preventing or intercepting RAS-mutated tumors.
  • Prevention and interception represent viable strategies for managing RAS-driven cancers.
  • Future research could explore vaccines targeting KRAS as an alternative prevention approach.

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