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| Open AccessDisentangling oncogenic amplicons in esophageal adenocarcinoma
Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.
- Alvin Wei Tian Ng
- , Dylan Peter McClurg
- & Rebecca C. Fitzgerald
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Article
| Open AccessMesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
- Cristiana Spinelli
- , Lata Adnani
- & Janusz Rak
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Article
| Open AccessThe EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Eukaryotic initiation translation factor 3 subunit h (EIF3H) possesses an alternative “moonlighting” function of deubiquitinase, while its role in colorectal carcinogenesis remains to be explored. Here the authors show that EIF3H deubiquitinates and stabilizes HAX1, which enhances RAF-MEK-ERK signaling to promote colorectal tumor growth and metastasis.
- Huilin Jin
- , Xiaoling Huang
- & Mong-Hong Lee
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Article
| Open AccessOncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner
Here the authors report that oncogenic c-Myc induces replication stress via increasing the amount of cohesins bound to chromatin at CTCF sites.
- Silvia Peripolli
- , Leticia Meneguello
- & Robertus A. M. de Bruin
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Article
| Open AccessThe Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation
The Eyes Absent proteins (EYA1-4) are a group of tyrosine phosphatases. Here, the authors report a signalling pathway in which EYA4 and EYA1 dephosphorylate Polo-like kinase 1 (PLK1) at pY445 to support PLK1 activation and mitosis.
- Christopher B. Nelson
- , Samuel Rogers
- & Hilda A. Pickett
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Article
| Open AccessOncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis
The molecular mechanisms of lung cancer metastasis remain incompletely understood. Here the authors show that the transcription factor ZBTB11 drives metastasis in preclinical models of lung cancer both through SE translocation (SET)-dependent and independent manner.
- Wenbin Xu
- , Han Yao
- & Donglai Wang
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Article
| Open AccessG-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis
G-quadruplexes (G4s) can recruit transcription factors to activate genes. Here, the authors revealed that G4s drive molecular motility in phase-separated condensates of MAZ and coactivators, leading to activated CCND1 expression in liver cancer.
- Wenmeng Wang
- , Dangdang Li
- & Guangchao Sui
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Article
| Open AccessNuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma
The MYC oncogene is activated in the majority of human cancers and has proven challenging to target therapeutically. In this study, the authors identify genome-wide MYC synthetic-lethal interactions that could serve as potential alternative targets for the treatment of MYC-driven cancers.
- Anja Deutzmann
- , Delaney K. Sullivan
- & Dean W. Felsher
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Article
| Open AccessAKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
The metabolic switch of tumours to aerobic glycolysis can allow them to meet their increasing energetic demands. Here, the authors show that AKT1 regulates this switch through the phosphorylation of malic enzyme 2 (ME2) preventing mitochondrial translocation. In turn this pushes the cell from mitochondrial metabolism to glycolysis, promoting tumour growth.
- Taiqi Chen
- , Siyi Xie
- & Wenjing Du
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Article
| Open AccessFunctional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance
The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Harish N. Vasudevan
- , Emily Payne
- & David R. Raleigh
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Article
| Open AccessKRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo
The function of wild-type KRAS in KRAS mutant cancers remains to be explored. Here, the authors show that deletion of the tumour-suppressive wild-type Kras in a KRASG12D driven colon cancer model exacerbates tumour initiation in a MAPK dependent manner, while acting to suppress metastasis through impaired immune suppression.
- Arafath K. Najumudeen
- , Sigrid K. Fey
- & Owen J. Sansom
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Article
| Open AccessConformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition
The authors use an integrative structural biology approach to elucidate molecular features of the RAS Q61 family of public tumor antigens. This information can be used to develop targeted therapeutics to combat a range of cancers.
- Andrew C. McShan
- , David Flores-Solis
- & Nikolaos G. Sgourakis
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Article
| Open AccessOncogenic context shapes the fitness landscape of tumor suppression
Alterations in oncogenes and tumor suppressor genes are a hallmark of cancer, yet how they interact remains poorly understood. Here, the authors describe a quantitative functional cancer genomics platform in genetically engineered mice, and uncover complex interactions between tumor suppressors and KRAS, BRAF, and EGFR oncogenes across more than 100 different lung tumor genotypes.
- Lily M. Blair
- , Joseph M. Juan
- & Ian P. Winters
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Article
| Open AccessIGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia
Additional roles of metabolic enzymes in cancer remain to be explored. Here, the authors show nuclear localized PYCR1 undergoes IGF1R-mediated phosphorylation under hypoxia, binds with ELK4 and recruits SIRT7 to modulate transcription of target genes to promote colorectal cancer progression.
- Ke Zheng
- , Nannan Sha
- & Tao Chen
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Article
| Open AccessCritical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma
Critical regulators of RAS signaling pathways in oncogenic RAS-driven tumors remain to be explored. Here, the authors show the development of KRAS(G12D)-driven lung adenocarcinoma is dependent on SOS1, with dual roles in both tumor and stroma.
- Fernando C. Baltanás
- , Rósula García-Navas
- & Eugenio Santos
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Article
| Open AccessTrim33 masks a non-transcriptional function of E2f4 in replication fork progression
Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.
- Vanessa Rousseau
- , Elias Einig
- & Nikita Popov
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Article
| Open AccessCryo-EM structure of a RAS/RAF recruitment complex
RAF kinases are autoinhibited in the cytosol and are activated by recruitment to the plasma membrane by GTP-bound RAS. Here, the authors describe cryoEM structures of a membrane-free KRAS/BRAF/MEK/14-3-3 complex that capture a pre-activation intermediate with BRAF still in an autoinhibited state.
- Eunyoung Park
- , Shaun Rawson
- & Michael J. Eck
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Article
| Open AccessAtomic model for core modifying region of human fatty acid synthase in complex with Denifanstat
Here, the authors develop a protein engineering method that enables high-resolution structural biology study of human fatty acid synthase. Using this technique, they uncover unique structural features of the enzyme and the mechanism of its inhibition by an anticancer drug Denifanstat.
- S. M. Naimul Hasan
- , Jennifer W. Lou
- & Mohammad T. Mazhab-Jafari
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Article
| Open AccessIn vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
There is still a limited understanding of mechanisms of sensitivity/resistance to cancer immunotherapy. Here the authors perform in vivo CRISPR/Cas9 loss-of-function screens in mouse lung cancer models, revealing Serpinb9 and Adam2 as regulators of immunotherapy response.
- Dzana Dervovic
- , Ahmad A. Malik
- & Daniel Schramek
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Article
| Open AccessHyperphosphorylated PTEN exerts oncogenic properties
PTEN has tumor suppressive functions. Here the authors report that PTEN C-tail hyperphosphorylation promotes neoplastic growth through oncogenic activation of WNT signalling.
- Janine H. van Ree
- , Karthik B. Jeganathan
- & Jan M. van Deursen
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Article
| Open AccessDNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC
DNA polymerase 1 (POLD1) has an important role in DNA damage repair and is frequently upregulated in cancer. Here, the authors report a non-canonical role of POLD1 wherein it stabilises MYC protein, creating a positive feedback loop with POLD1 expression and driving bladder cancer progression and metastasis.
- Yejinpeng Wang
- , Lingao Ju
- & Xinghuan Wang
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Article
| Open AccessOncogenic drivers dictate immune control of acute myeloid leukemia
There is increasing evidence of a functional interaction between acute myeloid leukemia (AML) and immune cells, influencing disease outcome. Here the authors study how distinct oncogenes differentially affect the host immune response to leukemic cells in preclinical models of AML.
- Rebecca J. Austin
- , Jasmin Straube
- & Megan J. Bywater
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Article
| Open AccessDomain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities
Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy.
- Teresa Lai Fong Ho
- , May Yin Lee
- & Ashok R. Venkitaraman
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Article
| Open AccessSOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry
The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.
- Bieke Decaesteker
- , Amber Louwagie
- & Frank Speleman
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Article
| Open AccessNon-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
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Article
| Open AccessGlycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
KRAS is a small GTPase that regulates cell proliferation. Here, the authors show that a subset of cell surface glycosphingolipids regulate KRAS plasma membrane localization by modulating inner leaflet lipid composition, uncovering a requirement for KRAS oncogenesis that may have therapeutic potential.
- Junchen Liu
- , Ransome van der Hoeven
- & John F. Hancock
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Article
| Open AccessTumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation
YTHDF1 is an m6A reader that binds to methylated RNA and facilitates translation. Here the authors show that tumor intrinsic YTHDF1 promotes tumorigenesis by regulating lysosomal proteolysis of MHC-I and that YTHDF1 targeting boosts anti-tumor immunity and response to immunotherapy in preclinical cancer models.
- Wanzun Lin
- , Li Chen
- & Jiade J. Lu
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Article
| Open AccessERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II
Growth factor-induced release of RNA Pol-II promoter-proximal pausing is vital for immediate-early gene expression, but its mechanism remains elusive. Here, the authors reveal roles of ERK and PP2A in this process and their dysregulation in cancer.
- Seina Ohe
- , Yuji Kubota
- & Mutsuhiro Takekawa
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Article
| Open AccessStromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis
Prostate stromal cells can contribute to prostate tumorigenesis. Here the authors show that the loss of androgen receptor signalling in Gli1-lineage stromal cells diminishes prostate epithelial oncogenic transformation and tumor growth in mouse models and this is due to insulin-like growth factor binding protein 3-mediated inhibiting IGF1 and Wnt/β-catenin signalling activation.
- Alex Hiroto
- , Won Kyung Kim
- & Zijie Sun
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Article
| Open AccessCharacterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma
The biological and clinical implications of high genome instability in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, the authors analyse 528 whole genomes and investigate the landscape and molecular mechanisms underlying structural variations in ESCC patients.
- Heyang Cui
- , Yong Zhou
- & Qimin Zhan
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Article
| Open AccessModeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers
Identifying structural variants (SVs) under positive selection in cancer is challenging. Here, the authors develop CSVDriver, a method that computes SV breakpoint proximity and the contribution of elements such as topologically associating domains, and identifies loci that show signs of positive selection and contain known and putative drivers.
- Alexander Martinez-Fundichely
- , Austin Dixon
- & Ekta Khurana
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Article
| Open AccessThe comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations
Frequency of cancer-related gene mutations can vary between populations. Here, the authors show differences in TP53 and other gene mutations between the U.S. and Chinese patients, and analyse differences in environmental risk factors to demonstrate that population-specific factors should be considered when discussing cancer risk.
- Fayang Ma
- , Kyle Laster
- & Zigang Dong
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Article
| Open AccessARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer
ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated colorectal cancer tumors, however, its relationship with treatment response remains to be explored. Here, the authors suggest that ARID1A mutations may confer intrinsic and acquired resistance to cetuximab treatment.
- Radia M. Johnson
- , Xueping Qu
- & Carlos Bais
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Article
| Open AccessOncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.
- Yandan Yang
- , Arnold Bolomsky
- & Ryan M. Young
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Article
| Open AccessTherapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen
Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.
- Andrew Poole
- , Vijaykumar Karuppiah
- & Chandramouli Chillakuri
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Article
| Open AccessCK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
Hippo signalling is often deregulated in cancers. Here the authors show that CK2 enhances the cooperation of HHEX with YAP-TEAD complex to promote colorectal tumorigenesis.
- Yuegui Guo
- , Zhehui Zhu
- & Chen-Ying Liu
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Article
| Open AccessUltra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.
- M. Kyle Cromer
- , Valentin V. Barsan
- & Matthew H. Porteus
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Article
| Open AccessMYC sensitises cells to apoptosis by driving energetic demand
MYC activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.
- Joy Edwards-Hicks
- , Huizhong Su
- & Andrew J. Finch
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Article
| Open AccessAberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes
Activation of the androgen receptor (AR) through androgen binding is essential for prostate tumorigenesis. Here the authors show that AR activation in a subpopulation of prostatic progenitor cells can initiate prostatic intraepithelial neoplasia formation and promotes prostate cancer development through activation of IGF1 and Wnt/β-catenin signalling pathways.
- Won Kyung Kim
- , Adam W. Olson
- & Zijie Sun
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Article
| Open AccessOncogenic BRAF induces whole-genome doubling through suppression of cytokinesis
Whole-genome doubling (WGD) commonly occurs in many solid tumors. Here the authors use a zebrafish model of melanoma and in vitro models to show that BRAFV600E induces WGD via inhibition of RhoA and cytokinesis failure.
- Revati Darp
- , Marc A. Vittoria
- & Craig J. Ceol
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Article
| Open AccessQualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
MEK1 mutations are found in cancer and RASopathies, but their effects remain unclear. Here, the authors reveal a mutant MEK1 structure and qualitative differences in biological properties between the cancer- and RASopathy-associated mutants, providing insights into the pathophysiology, diagnosis, and treatment of these diseases.
- Yuji Kubota
- , Yuko Fujioka
- & Mutsuhiro Takekawa
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Article
| Open AccessInactivation of the Hippo tumor suppressor pathway promotes melanoma
Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation.
- Marc A. Vittoria
- , Nathan Kingston
- & Neil J. Ganem
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Article
| Open AccessRNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer
The influence of mRNA splicing on colon cancer development and progression is unclear. In this study, the authors demonstrate that the SRSF1 splicing factor is essential to sustain the stem cell phenotype of WNT-activated colorectal cancers.
- Adam E. Hall
- , Sebastian Öther-Gee Pohl
- & Kevin B. Myant
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Article
| Open AccessAIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis
Direct targeting of oncogenic KRAS activity is a challenge. Here the authors report that a splice variant of AIMP2, AIMP2-DX2, enhances KRAS stability by blocking ubiquitin-mediated degradation of KRAS via the E3 ligase, Smurf2, and identify a chemical that can hinder AIMP2-DX2 from interacting with KRAS.
- Dae Gyu Kim
- , Yongseok Choi
- & Sunghoon Kim
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Article
| Open AccessIRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma
IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition.
- Stella Amanda
- , Tze King Tan
- & Takaomi Sanda
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Article
| Open AccessAKT mutant allele-specific activation dictates pharmacologic sensitivities
How different oncogenic Akt mutants can affect the response to Akt inhibitors is currently unclear. Here, the authors analyse somatic mutations of Akt1-3 isoforms in several human cancers, investigate their oncogenic effects and therapeutic relevance in vitro and confirm some of their data in a clinical trial testing the AKT inhibitor capivasertib in patients with solid tumors harboring AKT alterations.
- Tripti Shrestha Bhattarai
- , Tambudzai Shamu
- & Barry S. Taylor
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Article
| Open AccessNuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
The mechanisms behind the oncogenic role of the PIK3CA helical domain mutant is poorly understood. Here, the authors show that its oncogenic function depends on the release of p85β from mutated p110α, its translocation to the nucleus and the consequent increased activity of EZH proteins.
- Yujun Hao
- , Baoyu He
- & Zhenghe Wang
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Article
| Open AccessMultilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
RNA binding proteins (RBPs) can participate in regulatory networks to control alternative splicing. Here the authors show that DAP3 functions as an RBP splicing modulator via two mechanisms, and that its overexpression leads to mis-splicing events in cancers.
- Jian Han
- , Omer An
- & Leilei Chen
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Article
| Open AccessS6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
The direct upstream regulation of PDK1 is not fully understood. Here the authors demonstrate that S6K1 directly phosphorylates PDK1 to inhibit AKT kinase activity and its ability to drive tumourigenesis.
- Qiwei Jiang
- , Xiaomei Zhang
- & Jianping Guo