Reply: Somatic mutations are present in all members of the AKT family in endometrial carcinoma

Abstract

Cancer Research UK Sir,We appreciate the attention given by Drs Dutt, Salvesen, Greulich, Sellers, Beroukhim and Meyerson to our recent publication 'The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas ' (Shoji et al, 2009). In this article, we report a 2% mutational frequency of AKT1 (E17K) among 101 endometrial carcinomas. We also described that these two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. Our report has proposed two issues to be clarified: (1) Are there any 'oncogenic' mutations in other AKT family members in endometrial carcinomas? (2) Are all the AKT family mutations mutually exclusive with other PI3 kinase-AKT-activating mutations?Including the data in their earlier report, Dutt et al (2008) revealed mutations in AKT2 and AKT3, as well as in AKT1. As for AKT1 (E17K) mutations, their data and our data are compatible, showing that AKT1 mutations were detected in 2% of the endometrioid subtype in endometrial cancer. Compared with the accumulative data in AKT1 (E17K) mutations, mutations in AKT2 and AKT3 are not well characterised. Carpten et al (2007) and Kim et al (2008) reported no E17K mutations in AKT2 and AKT3 in breast, colorectal, gastric, hepatocellular, lung carcinomas and acute leukaemias. Davies et al (2008) first reported AKT3 (E17K) mutations in melanoma at 1.5% frequency. Parsons et al (2005) found two mutations of AKT2 (S302G and R371H) in 204 colorectal cancer samples, and Soung et al (2006) reported one missense mutation (A377V) and two possible splice-site mutations in intron 11 of AKT2 in gastric and lung adenocarcinoma. However, the physiological role of AKT2 mutations, including those (D399N, R368C and D32H) reported by Dutt et al (2008), has not been validated yet. In addition, the AKT3 (E438D) mutation has not been reported in any type of tumours. It is important to clarify whether these rare AKT2/3 mutations cause an oncogenic effect in cancer.We previously reported that PIK3CA mutations frequently coexist with mutations in PTEN and/or KRAS, and suggested that the PIK3CA mutation might require another upstream input to fully activate the PI3K kinase -AKT pathway (Oda et al, 2005(Oda et al, , 2008. Their data of coexistent mutations in AKT1 (E17K) and KRAS (G13D) suggest that the KRAS mutation alone is insufficient for a full activation of the PI3 kinase -AKT pathway. Their data are not inconsistent with the hypothesis that the AKT1 (E17K) mutation and the PIK3CA mutation are mutually exclusive. The coexistent mutations of AKT3 and PIK3CA in one sample suggest that some types of AKT mutations (non-E17K) might coexist with PIK3CA mutations to enhance the activation of the PI3 kinase -AKT pathway. Further analyses are necessary to clarify the frequency of coexistent mutations in AKT1 (E17K), AKT2/3 and other mutations.Their current data and our data suggest that the PI3 kinase -AKT pathway is prevalently activated in endometrial cancer through various genetic alterations and their combinations. Further analyses...

Targeting Functional Activity of AKT Has Efficacy against Aggressive Neuroblastoma

“…By mining publicly available data and reviewing the literature, we did not find any documented molecular alteration of the AKT isoforms in neuroblastoma. In contrast, in different adult cancers such as lung, breast, and endometrial cancers or melanoma mutations in AKT1 – 3 have been discovered. − While AKT mutations predicting AKT inhibitor sensitivity remains to be tested in the clinic, upregulation of AKT3 has already been reported to confer resistance in small-molecule pan-AKT inhibitor MK-2206 in breast cancer . In this study, we were not able to detect AKT3 protein expression in a panel of neuroblastoma cell lines tested, and our results demonstrated that AKT1 and 2 isoforms did not regulate neuroblastoma cell proliferation in a specific manner by contrast with previous data reporting distinct roles of AKT isoforms in regulating breast, lung, or prostate cancer cell proliferation, migration, or survival. − , One possible explanation could be AKT isoform compensation.…”

“…AKT drives oncogenic regulation of MYCN through GSK3β providing a therapeutic rationale to inhibit this pathway in MYCN -amplified neuroblastoma. , Preclinical and clinical trials testing AKT inhibitors are ongoing to assess whether their potential will translate to clinical efficacy. , Improved understanding of the specific functions attributed to the three AKT isoforms in cancer has actively contributed to developing ATP-competitive or allosteric AKT inhibitors targeting specific isoform of AKT or total AKT protein . Indeed, in different solid tumors such as breast, prostate, or lung cancers, AKT isoform-specific or -selective substrate phosphorylation has been demonstrated. − Moreover, mutations or amplification in AKT1 – 3 have been reported in different adult cancers such as lung, breast, and endometrial cancers or melanoma. − In neuroblastoma, no molecular alteration of the AKT isoforms has yet been reported. Opel et al showed that activation of AKT correlates with poor prognosis in primary neuroblastoma .…”

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

“…A gain of function mutation in KRAS activates both the mitogen‐activated protein kinase (MAPK) pathway and the PI3K pathway, whereas a loss of function mutation in PTEN activates the PI3K pathway . In addition to these alterations, we found various types of mutations in the RAS/PI3K pathway, including PIK3CA , AKT1 , and reduction in the chromosomal copy number of NF1 (a negative regulator of RAS) . Increased alteration in the activation of the RAS/PI3K pathway was confirmed based on TCGA .…”