Recurrent AKT mutations in human cancers: functional consequences and effects on drug sensitivity.

Kyung H Yi,Josh Lauring

doi:10.18632/oncotarget.6648

Abstract

Precision oncology trials based on tumor gene sequencing depend on robust knowledge about the phenotypic consequences of the genetic variants identified in patients' tumors. Mutations in AKT1-3 occur in 3-5% of human cancers. Although a single hotspot mutation, E17K, is the most common, well characterized activating mutations account for a minority of Akt variants that have been identified in large tumor sequencing studies to date. In order to determine the potential clinical relevance of both common and rare Akt mutations, we expressed a set of over twenty recurrent Akt mutants in three different cell lines and evaluated activation of Akt pathway signaling and effects on growth. We determined their relative sensitivity to allosteric and ATP-competitive Akt inhibitors in clinical development. Most Akt mutants did not activate pathway signaling compared to wild type Akt and did not affect growth properties. In addition, the most common activating Akt mutations, including Akt1 E17K, L52R, and Q79K conferred neither sensitivity nor resistance to Akt inhibitors. Equivocal evidence was found that Akt1 D323H and Akt2 W80C mutants are relatively resistant to the allosteric Akt inhibitor MK-2206, but not an ATP-competitive inhibitor. Our results suggest that the vast majority of rare Akt variants are passenger mutations with no effect on drug sensitivity. The hypothesis that activating Akt mutations predict for Akt inhibitor sensitivity remains to be tested clinically, but is not yet supported by our preclinical data.

Highlights

With the recent explosion in knowledge of cancer genetics and widespread availability of tumor whole exome or targeted sequencing for clinical decisionmaking, large clinical trial efforts are underway to implement personalized or “precision” oncology approaches
We curated a dataset of mutations in AKT1-3 from COSMIC, TCGA, and individual tumor sequencing studies reported in the literature [3, 7, 8]
Some of the mutants chosen for study occur in AKT3, we used only AKT1 and AKT2 for our analysis, since all of these AKT3 mutants had a homologous mutant in AKT1 or AKT2

Summary

Introduction

With the recent explosion in knowledge of cancer genetics and widespread availability of tumor whole exome or targeted sequencing for clinical decisionmaking, large clinical trial efforts are underway to implement personalized or “precision” oncology approaches. A small percentage of B-Raf mutant cancers have non-V600 mutations which have been shown to result in a kinasedead form of B-Raf that activates the MAPK pathway via C-Raf [1]. Such mutants are not sensitive to the B-Raf V600-specific inhibitors vemurafenib and dabrafenib. Preclinical functional analysis may serve in the interim to provide the best available evidence for matching gene variants to targeted therapies

Methods

Results

Conclusion