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

Omer 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

4 Citations (Scopus)

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
Pages (from-to)53-62
Number of pages10
JournalCancer Biology and Therapy
Volume19
Issue number1
DOIs
Publication statusPublished - 2 Jan 2018
Externally publishedYes

Fingerprint

Melanoma
RNA Interference
Cell Cycle Checkpoints
DNA Repair
DNA Damage
Cell Survival
Transcription Factors
Phosphotransferases
Therapeutics
Neoplasms

Keywords

  • AKT3
  • Melanoma
  • synergy
  • WEE1

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Kuzu, O., Gowda, R., Sharma, A., Noory, M. A., Kardos, G., Madhunapantula, S. R. V., ... Robertson, G. P. (2018). Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. Cancer Biology and Therapy, 19(1), 53-62. https://doi.org/10.1080/15384047.2017.1360446

Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. / Kuzu, Omer; Gowda, Raghavendra; Sharma, Arati; Noory, Mohammad A.; Kardos, Gregory; Madhunapantula, Subba Rao V.; Drabick, Joseph J.; Robertson, Gavin P.

In: Cancer Biology and Therapy, Vol. 19, No. 1, 02.01.2018, p. 53-62.

Research output: Contribution to journalArticle

Kuzu, O, Gowda, R, Sharma, A, Noory, MA, Kardos, G, Madhunapantula, SRV, Drabick, JJ & Robertson, GP 2018, 'Identification of WEE1 as a target to make AKT inhibition more effective in melanoma', Cancer Biology and Therapy, vol. 19, no. 1, pp. 53-62. https://doi.org/10.1080/15384047.2017.1360446
Kuzu, Omer ; Gowda, Raghavendra ; Sharma, Arati ; Noory, Mohammad A. ; Kardos, Gregory ; Madhunapantula, Subba Rao V. ; Drabick, Joseph J. ; Robertson, Gavin P. / Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. In: Cancer Biology and Therapy. 2018 ; Vol. 19, No. 1. pp. 53-62.
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