PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001.
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 alpha 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.
Mohseni
Morassa
M
Breast Cancer Research Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Park
Ben Ho
BH
D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000235:genetics*
D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human