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 language | English (US) |
|---|---|
| Pages (from-to) | 53-62 |
| Number of pages | 10 |
| Journal | Cancer Biology and Therapy |
| Volume | 19 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2 2018 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Oncology
- Pharmacology
- Cancer Research
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Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. / Kuzu, Omer F.; Gowda, Raghavendra; Sharma, Arati; Noory, Mohammad A.; Kardos, Gregory; Madhunapantula, Subba Rao V.; Drabick, Joseph; Robertson, Gavin.
In: Cancer Biology and Therapy, Vol. 19, No. 1, 02.01.2018, p. 53-62.Research output: Contribution to journal › Article
TY - JOUR
T1 - Identification of WEE1 as a target to make AKT inhibition more effective in melanoma
AU - Kuzu, Omer F.
AU - Gowda, Raghavendra
AU - Sharma, Arati
AU - Noory, Mohammad A.
AU - Kardos, Gregory
AU - Madhunapantula, Subba Rao V.
AU - Drabick, Joseph
AU - Robertson, Gavin
PY - 2018/1/2
Y1 - 2018/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85035750339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035750339&partnerID=8YFLogxK
U2 - 10.1080/15384047.2017.1360446
DO - 10.1080/15384047.2017.1360446
M3 - Article
C2 - 28853983
AN - SCOPUS:85035750339
VL - 19
SP - 53
EP - 62
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 1
ER -