PIK3CA and KRAS mutations predict for response to everolimus therapy: now that’s RAD001
Morassa Mohseni, Ben Ho Park
Morassa Mohseni, Ben Ho Park
Published July 26, 2010
Citation Information: J Clin Invest. 2010;120(8):2655-2658. https://doi.org/10.1172/JCI44026.
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Commentary

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

Abstract

Targeted cancer therapeutics can be effective when patients are preselected to maximize the chance of response. Increasingly, molecular markers such as oncogenic DNA mutations are being exploited to help guide patient preselection. These DNA lesions can predict for either a positive or negative response to a given drug. Finding such predictive biomarkers is an ongoing challenge. New work by Di Nicolantonio and colleagues in this issue of the JCI demonstrates that PI3K catalytic α subunit (PIK3CA) mutations can sensitize cancer cells to the mammalian target of rapamycin (mTOR) inhibitor everolimus. In addition, they show that the concurrent presence of PIK3CA mutations and mutations in either KRAS or BRAF predict for resistance to this drug. These data suggest that mTOR inhibitors currently in use will be ineffective against cancers that have a mutation in either KRAS or BRAF despite having PI3K/AKT/mTOR pathway activation.

Authors

Morassa Mohseni, Ben Ho Park

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Figure 2

Predicting responses using genetically engineered isogenic human cell lines.

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Predicting responses using genetically engineered isogenic human cell li...
Human mammary epithelial cells (WT) are subjected to gene targeting to create isogenic derivatives that contain a single PIK3CA oncogenic mutation (Mutant knock-in) or the same PIK3CA mutation along with a KRAS oncogenic mutation (Mutant double knock-in). Cells are then subjected to drugs in parallel, and resistance versus sensitivity can be assessed. Because the cell lines are isogenic, this allows for a clean interpretation of whether drug sensitivity is mediated by the presence or absence of a given mutation or set of mutations.