bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2022‒09‒04
eighteen papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute
  1. The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane.
  2. Signal amplification in growth cone gradient sensing by a double negative feedback loop among PTEN, PI(3,4,5)P3 and actomyosin.
  3. A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.
  4. DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
  5. Operation of a TCA cycle subnetwork in the mammalian nucleus.
  6. Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk.
  7. Mitochondria in cancer: clean windmills or stressed tinkerers?
  8. LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.
  9. Imaging and analysis for simultaneous tracking of fluorescent biosensors in barcoded cells.
  10. SLC4A7 and mTORC1 raise nucleotide synthesis with bicarbonate.
  11. scAllele: A versatile tool for the detection and analysis of variants in scRNA-seq.
  12. Mosaicism in Tuberous Sclerosis Complex - Lowering the Threshold for Clinical Reporting.
  13. Spatiotemporal NF-κB dynamics encodes the position, amplitude, and duration of local immune inputs.
  14. Cloud-enabled Biodepot workflow builder integrates image processing using Fiji with reproducible data analysis using Jupyter notebooks.
  15. CoRa-A general approach for quantifying biological feedback control.
  16. Editor's Note: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer.
  17. A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer.
  18. Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state.
  1. J Biol Chem. 2022 Aug 27. pii: S0021-9258(22)00880-8. [Epub ahead of print] 102437
    The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane.
    Mei-Ling Li, Aparna Ragupathi, Nikhil Patel, Tatiana Hernandez, Jedrick Magsino, Guy Werlen, Gary Brewer, Estela Jacinto.
      mTOR, which is part of mTOR complex 1 (mTORC1) and mTORC2, controls cellular metabolism in response to levels of nutrients and other growth signals. A hallmark of mTORC2 activation is the phosphorylation of Akt, which becomes upregulated in cancer. How mTORC2 modulates Akt phosphorylation remains poorly understood. Here, we found that the RNA binding protein, AUF1 (ARE/poly(U)-binding/degradation factor 1), modulates mTORC2/Akt signaling. We determined that AUF1 is required for phosphorylation of Akt at Thr308, Thr450, and Ser473, and that AUF1 also mediates phosphorylation of the mTORC2-modulated metabolic enzyme GFAT1 at Ser243. Additionally, AUF1 immunoprecipitation followed by qRT-PCR revealed that the mRNAs of Akt, GFAT1, and the mTORC2 component SIN1 associate with AUF1. Furthermore, expression of the p40 and p45, but not the p37 or p42, isoforms of AUF1 specifically mediate Akt phosphorylation. In the absence of AUF1, subcellular fractionation indicated that Akt fails to localize to the membrane. However, ectopic expression of a membrane-targeted allele of Akt is sufficient to allow Akt-Ser473 phosphorylation despite AUF1 depletion. Finally, conditions that enhance mTORC2 signaling, such as acute glutamine withdrawal augment AUF1 phosphorylation while mTOR inhibition abolishes AUF1 phosphorylation. Our findings unravel a role for AUF1 in promoting membrane localization of Akt to facilitate its phosphorylation on this cellular compartment. Targeting AUF1 could have therapeutic benefit for cancers with upregulated mTORC2/Akt signaling.
    Keywords:  AUF1; Akt; RNA binding protein; glutamine; hnRNP D; mTOR; mTORC2
    DOI:  https://doi.org/10.1016/j.jbc.2022.102437
  2. Mol Cell Neurosci. 2022 Aug 30. pii: S1044-7431(22)00078-1. [Epub ahead of print] 103772
    Signal amplification in growth cone gradient sensing by a double negative feedback loop among PTEN, PI(3,4,5)P3 and actomyosin.
    Xiong Li, Sangwoo Shim, Katherine R Hardin, Kiran G Vanaja, Hongjun Song, Andre Levchenko, Guo-Li Ming, James Q Zheng.
      Axon guidance during neural wiring involves a series of precisely controlled chemotactic events by the motile axonal tip, the growth cone. A fundamental question is how neuronal growth cones make directional decisions in response to extremely shallow gradients of guidance cues with exquisite sensitivity. Here we report that nerve growth cones possess a signal amplification mechanism during gradient sensing process. In neuronal growth cones of Xenopus spinal neurons, phosphatidylinositol-3,4,5-trisphosphate (PIP3), an important signaling molecule in chemotaxis, was actively recruited to the up-gradient side in response to an external gradient of brain-derived neurotrophic factor (BDNF), resulting in an intracellular gradient with approximate 30-fold amplification of the input. Furthermore, a reverse gradient of phosphatase and tensin homolog (PTEN) was induced by BDNF within the growth cone and the increased PTEN activity at the down-gradient side is required for the amplification of PIP3 signals. Mechanistically, the establishment of both positive PIP3 and reverse PTEN gradients depends on the filamentous actin network. Together with computational modeling, our results revealed a double negative feedback loop among PTEN, PIP3 and actomyosin for signal amplification, which is essential for gradient sensing of neuronal growth cones in response to diffusible cues.
    Keywords:  Actin cytoskeleton; Asymmetric signaling; Axon guidance; Chemotaxis; Directional sensing; Phosphoinositide
    DOI:  https://doi.org/10.1016/j.mcn.2022.103772
  3. Future Oncol. 2022 Aug 30.
    A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.
    Jordi Rodón, Pauline Funchain, Theodore W Laetsch, Hendrik-Tobias Arkenau, Alice Hervieu, Christian F Singer, Yonina R Murciano-Goroff, Sant P Chawla, Kristin Anthony, Ikuo Yamamiya, Mei Liu, Abdel-Baset Halim, Karim A Benhadji, Osamu Takahashi, Suzette Delaloge.
      PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part Phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.
    Keywords:  Cowden syndrome; PTEN hamartoma tumor syndrome; PTEN inactivation; TAS-117; advanced solid tumor; clinical trial; germline PTEN mutation
    DOI:  https://doi.org/10.2217/fon-2022-0305
  4. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01098-1. [Epub ahead of print]40(9): 111278
    DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
    Christopher J Yuskaitis, Jinita B Modasia, Sandra Schrötter, Leigh-Ana Rossitto, Karenna J Groff, Christopher Morici, Divakar S Mithal, Ram P Chakrabarty, Navdeep S Chandel, Brendan D Manning, Mustafa Sahin.
      Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment.
    Keywords:  CP: Metabolism; CP: Neuroscience; GATOR1; SUDEP; TSC; amino acids; cell signaling; epilepsy; fasting; mTOR; metabolomics; seizures
    DOI:  https://doi.org/10.1016/j.celrep.2022.111278
  5. Sci Adv. 2022 Sep 02. 8(35): eabq5206
    Operation of a TCA cycle subnetwork in the mammalian nucleus.
    Eleni Kafkia, Amparo Andres-Pons, Kerstin Ganter, Markus Seiler, Tom S Smith, Anna Andrejeva, Paula Jouhten, Filipa Pereira, Catarina Franco, Anna Kuroshchenkova, Sergio Leone, Ritwick Sawarkar, Rebecca Boston, James Thaventhiran, Judith B Zaugg, Kathryn S Lilley, Christophe Lancrin, Martin Beck, Kiran Raosaheb Patil.
      Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
    DOI:  https://doi.org/10.1126/sciadv.abq5206
  6. Annu Rev Genomics Hum Genet. 2022 Aug 31. 23 331-361
    Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk.
    Jillian L Chen, David T Miller, Laura S Schmidt, David Malkin, Bruce R Korf, Charis Eng, David J Kwiatkowski, Krinio Giannikou.
      A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.
    Keywords:  NF1; NF2; PTEN; RB1; TP53; TSC1; TSC2; VHL; mosaicism; tumor suppressor
    DOI:  https://doi.org/10.1146/annurev-genom-120121-105450
  7. Trends Cell Biol. 2022 Aug 18. pii: S0962-8924(22)00191-X. [Epub ahead of print]
    Mitochondria in cancer: clean windmills or stressed tinkerers?
    Dario C Altieri.
      There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).
    Keywords:  Mic60; metabolism; metastasis; mitochondria; tumor plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.001
  8. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2205629119
    LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.
    Ying Wang, Jun Liu, Chizuru Akatsu, Runyun Zhang, Hai Zhang, Han Zhu, Kangwei Liu, Han-Ying Zhu, Qing Min, Xin Meng, Chaoqun Cui, Yue Tang, Meiping Yu, Yaxuan Li, Xiaoqian Feng, Hao Wei, Zichao Wen, Sihan Ji, Martin G Weigert, Takeshi Tsubata, Ji-Yang Wang.
      Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.
    Keywords:  B cell tolerance; E3 ubiquitin ligase; apoptosis; immature B cell; lysosomal-associated transmembrane protein 5
    DOI:  https://doi.org/10.1073/pnas.2205629119
  9. STAR Protoc. 2022 Sep 16. 3(3): 101611
    Imaging and analysis for simultaneous tracking of fluorescent biosensors in barcoded cells.
    Wei-Yu Chi, Gabriel Au, Jessica Liang, Chao-Cheng Chen, Chuan-Hsiang Huang, Jr-Ming Yang.
      We recently developed a biosensor barcoding approach for highly multiplexed tracking of molecular activities in live cells. In this protocol, we detail the labeling of cells expressing different genetically encoded fluorescent biosensors with a pair of barcoding proteins and parallel imaging. Signals from cells with the same barcodes are then pooled together to obtain the dynamics of the corresponding biosensor activity. We describe the steps involved in cell barcoding, image acquisition, and analysis by deep learning models. For complete details on the use and execution of this protocol, please refer to Yang et al. (2021).
    Keywords:  Cell biology; Microscopy; Molecular/Chemical probes; Signal transduction; Single cell
    DOI:  https://doi.org/10.1016/j.xpro.2022.101611
  10. Mol Cell. 2022 Sep 01. pii: S1097-2765(22)00763-8. [Epub ahead of print]82(17): 3121-3123
    SLC4A7 and mTORC1 raise nucleotide synthesis with bicarbonate.
    Jessica C Koe, Keeley G Hewton, Seth J Parker.
      In this issue of Molecular Cell, Ali et al. (2022) show that bicarbonate uptake by SLC4A7 fuels de novo nucleotide synthesis and cell proliferation and is regulated by mTORC1.
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.010
  11. Sci Adv. 2022 Sep 02. 8(35): eabn6398
    scAllele: A versatile tool for the detection and analysis of variants in scRNA-seq.
    Giovanni Quinones-Valdez, Ting Fu, Tracey W Chan, Xinshu Xiao.
      Single-cell RNA sequencing (scRNA-seq) data contain rich information at the gene, transcript, and nucleotide levels. Most analyses of scRNA-seq have focused on gene expression profiles, and it remains challenging to extract nucleotide variants and isoform-specific information. Here, we present scAllele, an integrative approach that detects single-nucleotide variants, insertions, deletions, and their allelic linkage with splicing patterns in scRNA-seq. We demonstrate that scAllele achieves better performance in identifying nucleotide variants than other commonly used tools. In addition, the read-specific variant calls by scAllele enables allele-specific splicing analysis, a unique feature not afforded by other methods. Applied to a lung cancer scRNA-seq dataset, scAllele identified variants with strong allelic linkage to alternative splicing, some of which are cancer specific and enriched in cancer-relevant pathways. scAllele represents a versatile tool to uncover multilayer information and previously unidentified biological insights from scRNA-seq data.
    DOI:  https://doi.org/10.1126/sciadv.abn6398
  12. Hum Mutat. 2022 Aug 28.
    Mosaicism in Tuberous Sclerosis Complex - Lowering the Threshold for Clinical Reporting.
    Zimeng Ye, Sufang Lin, Xia Zhao, Mark F Bennet, Natasha J Brown, Mathew Wallis, Xinyi Gao, Li Sun, Jiarui Wu, Ravikiran Vedururu, Tom Witkowski, Fiona Gardiner, Chloe Stutterd, Jing Duan, Saul A Mullen, George McGillivray, Simon Bodek, Giulia Valente, Matthew Reagan, Yi Yao, Lin Li, Li Chen, Amber Boys, Thiuni N Adikari, Dezhi Cao, Zhanqi Hu, Victoria Beshay, Victor W Zhang, Samuel F Berkovic, Ingrid E Scheffer, Jianxiang Liao, Michael S Hildebrand.
      Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and 8 families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital PCR. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction (VAF) 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling. (154/200 words) This article is protected by copyright. All rights reserved.
    Keywords:  Tuberous sclerosis complex; high-depth sequencing; mosaic mutations; parental mosaicism
    DOI:  https://doi.org/10.1002/humu.24454
  13. Sci Adv. 2022 Sep 02. 8(35): eabn6240
    Spatiotemporal NF-κB dynamics encodes the position, amplitude, and duration of local immune inputs.
    Minjun Son, Tino Frank, Thomas Holst-Hansen, Andrew G Wang, Michael Junkin, Sara S Kashaf, Ala Trusina, Savaş Tay.
      Infected cells communicate through secreted signaling molecules like cytokines, which carry information about pathogens. How differences in cytokine secretion affect inflammatory signaling over space and how responding cells decode information from propagating cytokines are not understood. By computationally and experimentally studying NF-κB dynamics in cocultures of signal-sending cells (macrophages) and signal-receiving cells (fibroblasts), we find that cytokine signals are transmitted by wave-like propagation of NF-κB activity and create well-defined activation zones in responding cells. NF-κB dynamics in responding cells can simultaneously encode information about cytokine dose, duration, and distance to the cytokine source. Spatially resolved transcriptional analysis reveals that responding cells transmit local cytokine information to distance-specific proinflammatory gene expression patterns, creating "gene expression zones." Despite single-cell variability, the size and duration of the signaling zone are tightly controlled by the macrophage secretion profile. Our results highlight how macrophages tune cytokine secretion to control signal transmission distance and how inflammatory signaling interprets these signals in space and time.
    DOI:  https://doi.org/10.1126/sciadv.abn6240
  14. Sci Rep. 2022 Sep 02. 12(1): 14920
    Cloud-enabled Biodepot workflow builder integrates image processing using Fiji with reproducible data analysis using Jupyter notebooks.
    Ling-Hong Hung, Evan Straw, Shishir Reddy, Robert Schmitz, Zachary Colburn, Ka Yee Yeung.
      Modern biomedical image analyses workflows contain multiple computational processing tasks giving rise to problems in reproducibility. In addition, image datasets can span both spatial and temporal dimensions, with additional channels for fluorescence and other data, resulting in datasets that are too large to be processed locally on a laptop. For omics analyses, software containers have been shown to enhance reproducibility, facilitate installation and provide access to scalable computational resources on the cloud. However, most image analyses contain steps that are graphical and interactive, features that are not supported by most omics execution engines. We present the containerized and cloud-enabled Biodepot-workflow-builder platform that supports graphics from software containers and has been extended for image analyses. We demonstrate the potential of our modular approach with multi-step workflows that incorporate the popular and open-source Fiji suite for image processing. One of our examples integrates fully interactive ImageJ macros with Jupyter notebooks. Our second example illustrates how the complicated cloud setup of an computationally intensive process such as stitching 3D digital pathology datasets using BigStitcher can be automated and simplified. In both examples, users can leverage a form-based graphical interface to execute multi-step workflows with a single click, using the provided sample data and preset input parameters. Alternatively, users can interactively modify the image processing steps in the workflow, apply the workflows to their own data, change the input parameters and macros. By providing interactive graphics support to software containers, our modular platform supports reproducible image analysis workflows, simplified access to cloud resources for analysis of large datasets, and integration across different applications such as Jupyter.
    DOI:  https://doi.org/10.1038/s41598-022-19173-w
  15. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2206825119
    CoRa-A general approach for quantifying biological feedback control.
    Mariana Gómez-Schiavon, Hana El-Samad.
      Feedback control is a fundamental underpinning of life, underlying homeostasis of biological processes at every scale of organization, from cells to ecosystems. The ability to evaluate the contribution and limitations of feedback control mechanisms operating in cells is a critical step for understanding and ultimately designing feedback control systems with biological molecules. Here, we introduce CoRa-or Control Ratio-a general framework that quantifies the contribution of a biological feedback control mechanism to adaptation using a mathematically controlled comparison to an identical system that does not contain the feedback. CoRa provides a simple and intuitive metric with broad applicability to biological feedback systems.
    Keywords:  control; feedback; homeostasis
    DOI:  https://doi.org/10.1073/pnas.2206825119
  16. Cancer Res. 2022 Sep 02. 82(17): 3188
    Editor's Note: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer.
    Toni M Brand, Stefan Hartmann, Neil E Bhola, Hua Li, Yan Zeng, Rachel A O'Keefe, Max V Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E Johnson, Michelle A Ozbun, Julie E Bauman, Jennifer R Grandis.
      
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1307
  17. Biochem Pharmacol. 2022 Aug 27. pii: S0006-2952(22)00327-6. [Epub ahead of print] 115233
    A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer.
    L Wester, S Venneker, M Hazenoot, C Pont, E Koedoot, A M Timmermans, J Martens, M P H M Jansen, C E M Kockx, W F J van Ijcken, J H N Meerman, Y Zhang, B van de Water.
      Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER+ breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.
    Keywords:  Breast cancer; EGFR; IGF1R; MEK inhibitors; selumetinib; tamoxifen resistance
    DOI:  https://doi.org/10.1016/j.bcp.2022.115233
  18. Elife. 2022 Aug 31. pii: e78012. [Epub ahead of print]11
    Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state.
    Caterina Carraro, Lorenzo Bonaguro, Jonas Schulte-Schrepping, Arik Horne, Marie Oestreich, Stefanie Warnat-Herresthal, Tim Helbing, Michele De Franco, Kristian Haendler, Sach Mukherjee, Thomas Ulas, Valentina Gandin, Richard Goettlich, Anna C Aschenbrenner, Joachim L Schultze, Barbara Gatto.
      Omics-based technologies are driving major advances in precision medicine, but efforts are still required to consolidate their use in drug discovery. In this work, we exemplify the use of multi-omics to support the development of 3-chloropiperidines, a new class of candidate anticancer agents. Combined analyses of transcriptome and chromatin accessibility elucidated the mechanisms underlying sensitivity to test agents. Furthermore, we implemented a new versatile strategy for the integration of RNA- and ATAC-seq (Assay for Transposase-Accessible Chromatin) data, able to accelerate and extend the standalone analyses of distinct omic layers. This platform guided the construction of a perturbation-informed basal signature predicting cancer cell lines' sensitivity and to further direct compound development against specific tumor types. Overall, this approach offers a scalable pipeline to support the early phases of drug discovery, understanding of mechanisms, and potentially inform the positioning of therapeutics in the clinic.
    Keywords:  chromatin accessibility; computational biology; drug candidate; human; mechanism of action; multi-omics; sensitivity ML prediction; systems biology; transcriptome
    DOI:  https://doi.org/10.7554/eLife.78012
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