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

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.

Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF/NRAS mutation status

“…The successful reduction of tumor growth rate by the combination was also observed in a xenograft mouse model, which indicates the combined treatment to be more promising from a clinical perspective. Moreover, we also show that WEE1 and IGF1R, previously suggested as targets to potentiate CMM therapy 33–35 , are downregulated in A375/SKMEl2 and A375/ESTDAB105, respectively, in response to the combination (Fig. 6k), and that silencing Wee1 reduces the combination-mediated effects on cell proliferation and migration.…”

Identification of Hub Genes Associated With Melanoma Development by Comprehensive Bioinformatics Analysis

“…In our study, FOXM1 was upregulated in tumor tissues compared to normal tissues, suggesting a significant correlation with melanoma. Previous studies have shown that higher levels of FOXM1 in tumor tissues have been strongly associated with low prognosis in melanoma patients, consistent with our study ( 33 – 35 ). Kinesin Family Member 20A (KIF20A) is also a protein-encoding gene, and what is known about the diseases associated with this gene is mainly familial restriction Familial Isolated Restrictive Cardiomyopathy and Charcot- Marie-Tooth Disease, Type 4C.…”

Identification of Hub Genes Associated with Melanoma Development by Comprehensive Bioinformatics Analysis

“…In our study, FOXM1 was upregulated in tumor tissues compared to normal tissues, suggesting a signi cant correlation with melanoma. Previous studies have shown that higher levels of FOXM1 in tumor tissues have been strongly associated with poor prognosis in melanoma patients, consistent with our study [33][34][35]. Kinesin Family Member 20A (KIF20A) is also a proteinencoding gene, and what is known about the diseases associated with this gene is mainly familial restriction Familial Isolated Restrictive Cardiomyopathy and Charcot-Marie-Tooth Disease, Type 4C.…”