Improving pharmacological targeting of AKT in melanoma

Omer Kuzu, Raghavendra Gowda, Arati Sharma, Mohammad A. Noory, Saketh S. Dinavahi, Gregory Kardos, Joseph J. Drabick, Gavin P. Robertson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Targeting AKT with pharmacological agents inhibiting this protein in the melanoma clinic is ineffective. This is a major contradiction considering the substantial preclinical data suggesting AKT as an effective target. Various approaches have been undertaken to unravel this contradiction and drug combinations sought that could resolve this concern. We have shown that genetic targeting AKT3 or WEE1 can be effective for inhibiting tumor growth in preclinical animal models. However, no one has examined whether combining pharmacological agents targeting each of these enzymes could be more effective than inhibiting each alone and enhance the efficacy of targeting AKT in melanoma. This report shows that combining the AKT inhibitors (AZD5363 or MK1775) with the WEE1 inhibitor, AZD5363, can synergistically kill cultured melanoma cells and decrease melanoma tumor growth by greater than 90%. Co-targeting AKT and WEE1 led to enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating the transcription factors p53 and FOXM1, as well as the proteins whose expression is regulated by these two proteins. Thus, this study identifies a unique combination of pharmacological agents and the ratio needed for efficacy that could be used to potentially improve the therapeutic effectiveness of targeting AKT in the clinic.

Original languageEnglish
Pages (from-to)29-36
Number of pages8
JournalCancer Letters
Volume404
DOIs
Publication statusPublished - 28 Sep 2017
Externally publishedYes

Fingerprint

Melanoma
Pharmacology
Proteins
Drug Combinations
Growth
DNA Repair
DNA Damage
Cultured Cells
Neoplasms
Cell Cycle
Transcription Factors
Animal Models
Enzymes
4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide
Therapeutics

Keywords

  • AKT3
  • AZD5363 and synergy
  • GDC0068
  • Melanoma
  • MK1775
  • WEE1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kuzu, O., Gowda, R., Sharma, A., Noory, M. A., Dinavahi, S. S., Kardos, G., ... Robertson, G. P. (2017). Improving pharmacological targeting of AKT in melanoma. Cancer Letters, 404, 29-36. https://doi.org/10.1016/j.canlet.2017.07.001

Improving pharmacological targeting of AKT in melanoma. / Kuzu, Omer; Gowda, Raghavendra; Sharma, Arati; Noory, Mohammad A.; Dinavahi, Saketh S.; Kardos, Gregory; Drabick, Joseph J.; Robertson, Gavin P.

In: Cancer Letters, Vol. 404, 28.09.2017, p. 29-36.

Research output: Contribution to journalArticle

Kuzu, O, Gowda, R, Sharma, A, Noory, MA, Dinavahi, SS, Kardos, G, Drabick, JJ & Robertson, GP 2017, 'Improving pharmacological targeting of AKT in melanoma', Cancer Letters, vol. 404, pp. 29-36. https://doi.org/10.1016/j.canlet.2017.07.001
Kuzu O, Gowda R, Sharma A, Noory MA, Dinavahi SS, Kardos G et al. Improving pharmacological targeting of AKT in melanoma. Cancer Letters. 2017 Sep 28;404:29-36. https://doi.org/10.1016/j.canlet.2017.07.001
Kuzu, Omer ; Gowda, Raghavendra ; Sharma, Arati ; Noory, Mohammad A. ; Dinavahi, Saketh S. ; Kardos, Gregory ; Drabick, Joseph J. ; Robertson, Gavin P. / Improving pharmacological targeting of AKT in melanoma. In: Cancer Letters. 2017 ; Vol. 404. pp. 29-36.
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