A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition

Cancer Discov. 2014 Jan;4(1):69-79. doi: 10.1158/2159-8290.CD-13-0279. Epub 2013 Nov 21.


BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptor, Platelet-Derived Growth Factor beta
  • AKT1 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt