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PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001

Morassa Mohseni1, Ben Ho Park

  • 1Breast Cancer Research Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.

The Journal of Clinical Investigation
|July 29, 2010
PubMed

Insights

PIK3CA mutations sensitize cancer cells to everolimus, an mTOR inhibitor. However, co-occurring KRAS or BRAF mutations predict resistance, suggesting mTOR inhibitors may be ineffective in these specific cancer types.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacogenomics

Background:

  • Targeted cancer therapies require patient preselection based on molecular markers.
  • Oncogenic DNA mutations serve as predictive biomarkers for drug response.
  • Identifying reliable predictive biomarkers remains a significant challenge in cancer treatment.

Purpose of the Study:

  • To investigate the predictive value of PIK3CA mutations in response to the mTOR inhibitor everolimus.
  • To determine if co-occurring mutations in KRAS or BRAF influence sensitivity or resistance to everolimus.
  • To assess the clinical implications of PIK3CA, KRAS, and BRAF mutations for mTOR inhibitor efficacy.

Main Methods:

  • Analysis of PIK3CA mutations in cancer cells.
  • Assessment of cellular response to everolimus.
  • Genomic analysis to identify co-occurring KRAS and BRAF mutations.

Main Results:

  • PIK3CA mutations were found to sensitize cancer cells to everolimus.
  • Concurrent PIK3CA and KRAS or BRAF mutations predicted resistance to everolimus.
  • Cancers with PIK3CA mutations alongside KRAS or BRAF mutations are unlikely to respond to current mTOR inhibitors.

Conclusions:

  • PIK3CA mutations can predict sensitivity to everolimus.
  • KRAS or BRAF co-mutations negate the efficacy of everolimus in PIK3CA-mutated cancers.
  • These findings highlight the complexity of predicting mTOR inhibitor response and the need for comprehensive biomarker analysis.

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