Identification of WEE1 as a target to make AKT inhibition more effective in melanoma

Omer F. Kuzu, Raghavendra Gowda, Arati Sharma, Mohammad A. Noory, Gregory Kardos, Subba Rao V. Madhunapantula, Joseph J. Drabick, Gavin P. Robertson

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65–75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma.

Original languageEnglish (US)
Pages (from-to)53-62
Number of pages10
JournalCancer Biology and Therapy
Volume19
Issue number1
DOIs
StatePublished - Jan 2 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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