AKT1 E17K

Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants...By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Typical morphologic structures, CK7(+), CK20(-), CDX2(-), p63(-), p40(-), MAML2 fluorescence in situ hybridization (-), AR(-), TTF-1(-), S100(-), mammaglobin(-), or S100/mammaglobin(+) with ETV6 fluorescence in situ hybridization (-) immunophenotype, and recurrent AKT1 E17K or BRAF V600E mutations may be defined. To our knowledge, this small series represents the first genetic study on a typical colloid pattern of MA, and our study with the spectrum documentation for MA in clinicopathologic characteristics, histologic and immunophenotypes, molecular features, and clinical behavior will allow for a better understanding of these rare but distinctive tumors.

Our findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

These findings may be attributed to the aberrant activation of the Akt/mTOR pathway due to AKT1 E17K mutations. Hence, both surface and round stromal cells have tumorigenic characteristics, and differences in these characteristics may contribute to variations in tumor growth and the morphology and angiogenesis of SP.

We further proposed that the SMAD4 protein loss may contribute to an aggressive phenotype by inhibiting the TGF-β signaling pathway. Thus, breast cancer's SMAD4 (V465M) mutation might increase their invasive and metastatic capabilities.Communicated by Ramaswamy H. Sarma.

Based on this CTC characteriza- tion, a targeted therapy including everolimus was selected. We propose that such a longitudinal and multiparametric analysis of liquid biopsies has the potential to identify individual targets for effective therapies, to monitor treatment response, and to optimize the clinical outcome eventually. Furthermore, from a scientific point of view, such studies can promote the understanding of the biology of CTCs during different treatment regimens and thereby further help to optimize treatment of all patients.

p16 and human papillomavirus (HPV) studies differentiate HPV-related squamous cell carcinoma from non-HPV-related neoplasms with overlapping features. NCOA4:RET fusion protein is the main fusion in intraductal carcinoma.

Cancer Type Total n of pts PR, n (mutation*, prior metastatic lines) SD†, n (prior metastatic lines) PD, n (prior metastatic lines) Non-CR/non-PD, n (prior metastatic lines) Non Evaluable, n Missing, n Breast 7 1 (AKT1:E17K, 5+) 4 (range 2–5+) 1 (3) 1 Prostate 7 4 (~3–4) 2 (4; 5+) 1 Colon 3 1 (4) 2 (3; 4) Colorectal 2 1 (PTEN loss, 3) 1 (2) Endometrial 2 1 (PTEN loss, 2) 1 Rectal 1 1 (1) Anal 2 1 (3) 1 (5+) Cervical 1 1 (2) Adenocarcinoma (Neck) 1 1 Grand Total, n 26 3 8 10 1 1 3 *High-level biomarker listed for PRs only here. Protocol-allowed biomarkers included mutations and PTEN loss via IHC and/or mutation †6 pts had SD >4 months

We also observed that, in parallel with an increased proliferation rate, tumors expressing mutant AKT1E17K presented an activation of the GSK3/cyclin D1 pathway in the mammary epithelium and cluster significantly with the human basal-like tumors. In conclusion, we demonstrate AKT1E17K is a bona fide oncogene that can initiate tumors at high efficiency in murine mammary epithelium in vivo.

In particular, they include gene fusions, which have shown to be tightly tumor-type specific, and thus valuable for use in diagnostically challenging cases. The recurrent molecular alterations were included in the definition of mucoepidermoid carcinoma, adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma, and microsecretory adenocarcinoma.

We describe 6 cases of salivary gland papillary adenocarcinoma with intestinal-like mucinous cytologic features, which are different from conventional intestinal-type adenocarcinoma, presenting a consistent immunophenotype of CK7 & MUC1 positive, CK20 & CDX2 negative and exhibiting recurrent AKT1 E17K mutations.

P1; Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations.

This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.

Higher frequencies of AKT1 mutation were observed in several common cancers, including cervical, breast, osteosarcoma, brain, head and neck and colorectal in our study . AKT1 E17K was more commonly found in breast, brain and cervical cancer . Given the fact that III/IV patients are more common in AKT1 mutated group, it coincides with AKT inhibitors therapeutic prospects in a variety of advanced malignant tumors .

In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

AKT1/CTNNB1 mutations were also associated with oxaliplatin, irinotecan, SN-38 and 5-fluorouracil resistance. Furthermore, mutant cell viability in oxaliplatin treatment was more effectively inhibited compared with that of the other chemotherapeutic drugs. In conclusion, AKT1/CTNNB1 mutations may be used as an important predictive biomarker in CRC treatment.

Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers. ClinicalTrials.gov Identifier: NCT00700882.

The results suggest that the use of AKT inhibitors in breast cancer patients could paradoxically accelerate metastatic progression in some genetic contexts and may explain the frequent co-selection for CDH1 mutations in AKT1 mutated breast tumors. Implications: AKT1 E17K mutation in breast cancer impairs migration/invasiveness via sequestration of β-catenin to the cell membrane leading to decreased ZEB1 transcription, resulting in increased E-cadherin expression and a reversal of epithelial-mesenchymal transition.

Our data suggested that underlying tumour genetics play a part in the development of the immune composition of the tumour microenvironment. Stratifying meningiomas by mutational status and correlating this with their cellular composition will aid in the development of new immunotherapies for patients.

In this review article, we describe how AKT1(E17K) mutations stimulate downstream signals that cause cells to emerge transformed; we explore the differential regulation and function of E17K in different physiological and pathological settings; and we also describe the phenomenon that E17K impedes tumor growth by interfering with growth-promoting and chemotherapy-resistant AKT1QCC generation, an intriguing finding that mutants may prolong tumor patient survival by activating feedback mechanisms and disrupting transcription. This review is intended to provide a better understanding of the role of AKT1(E17K) in cancer and to inform the development of AKT1(E17K)-based antitumor strategies.

MSI-H BC is rare but CGP can identify additional therapeutic options for rational combination with targeted therapies such as PI3K, PARP, and HER2 inhibitors. BRCA alterations may be of germline or somatic origin and they may be targetable, as demonstrated by gLOH, rather than passenger mutations. Further characterization of these tumors and comparison to both MSS BC and non-breast MSI-H tumor types, combined with treatment outcomes, can provide insights on rationale combinations and/or sequencing of therapeutic agents.

GP/MPs are characterized by AKT1 mutations concurrent with BRAF or HRAS mutations. Peribronchiolar papillary tumors with AKT1 mutations may also be classified as GP/MP.

Two mutations were identified in the tumor tissue by NGS and sanger sequencing: AKT1 E17K and BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600E. This is the first case report of a BRAF V600E mutation in a patient with SP. This discovery extends our understanding of the pathogenesis of SP, and suggests the need for future testing of BRAF V600E in this rare tumor type.

However, in absence of INI1 mutation, mechanisms for INI1 loss require further evaluation. Identification of AKT1 mutation opens up new avenues for targeted therapy in patients with such aggressive tumors.

Given that genes encoding components of a protein complex or a biological pathway often share similar phenotype upon genetic perturbation, we genetically depleted genes interacting with EGFR-PIK3CA-AKT kinases or DNA damage response proteins using siRNA or CRISPR/Cas9, and found multiple novel interacting genes whose depletion significantly alters AKT activation or PARPi/cisplatin sensitivity. This result not only functionally validates the physical protein interactions, but also demonstrates that our interactome mapping approach can helps identify new druggable vulnerabilities in breast cancer cells. We anticipate the breast cancer interactome study will uncover aberrant pathways and protein complexes operating in breast cancer cells, and thus pinpoint proteins that may potentially serve as distinct biomarkers or therapeutic targets for tumors having the same or similar subtypes and/or genomic mutations.

The expression of the AKT1 E17K mutation hotspot can inhibit the growth, proliferation, and survival ability of breast cancer cells, and promote apoptosis, while it also improves their migratory ability. The survival and prognosis of breast cancer patients with this mutation are good, which may be related to the inhibition of the PI3K/AKT/mTOR signaling pathway.

These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.