bims-pimaco 2023-08-20 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–08–20
seventeen papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.
Direct Modulators of K-Ras-Membrane Interactions.
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.
A sweet way to regulate cellular growth: OGT and mTOR join forces.
Structural mechanisms of the mTOR pathway.
Structural insights into the interaction of three Y-shaped ligands with PI3Kα.
FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1.
Next batter up! Targeting cancers with KRAS-G12D mutations.
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Facts and hopes on RAS inhibitors and cancer immunotherapy.
PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer.
One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids.
NEK8 regulates colorectal cancer progression via phosphorylating MYC.
Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation.
Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.
SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer.
Evolutionary history of MEK1 illuminates the nature of deleterious mutations.

Nat Metab. 2023 Aug 14.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

Johan Vande Voorde, Rory T Steven, Arafath K Najumudeen, Catriona A Ford, Alex Dexter, Ariadna Gonzalez-Fernandez, Chelsea J Nikula, Yuchen Xiang, Lauren Ford, Stefania Maneta Stavrakaki, Kathryn Gilroy, Lucas B Zeiger, Kathryn Pennel, Phimmada Hatthakarnkul, Efstathios A Elia, Ammar Nasif, Teresa Murta, Eftychios Manoli, Sam Mason, Michael Gillespie, Tamsin R M Lannagan, Nikola Vlahov, Rachel A Ridgway, Colin Nixon, Alexander Raven, Megan Mills, Dimitris Athineos, Georgios Kanellos, Craig Nourse, David M Gay, Mark Hughes, Amy Burton, Bin Yan, Katherine Sellers, Vincen Wu, Kobe De Ridder, Engy Shokry, Alejandro Huerta Uribe, William Clark, Graeme Clark, Kristina Kirschner, Bernard Thienpont, Vivian S W Li, Oliver D K Maddocks, Simon T Barry, Richard J A Goodwin, James Kinross, Joanne Edwards, Mariia O Yuneva, David Sumpton, Zoltan Takats, Andrew D Campbell, Josephine Bunch, Owen J Sansom.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

DOI: https://doi.org/10.1038/s42255-023-00857-0
ACS Chem Biol. 2023 Aug 14.

Direct Modulators of K-Ras-Membrane Interactions.

Johannes Morstein, Rebika Shrestha, Que N Van, César A López, Neha Arora, Marco Tonelli, Hong Liang, De Chen, Yong Zhou, John F Hancock, Andrew G Stephen, Thomas J Turbyville, Kevan M Shokat.

Protein-membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic interactions with the inner plasma membrane leaflet to populate and regulate signaling hotspots. Methods to target and modulate these interactions could yield attractive tool compounds and drug candidates. Here, we demonstrate that the conjugation of a medium-chain lipid tail to the covalent K-Ras(G12C) binder MRTX849 at a solvent-exposed site enables such direct modulation of PMIs. The conjugated lipid tail interacts with the tethered membrane and changes the relative membrane orientation and conformation of K-Ras(G12C), as shown by molecular dynamics (MD) simulation-supported NMR studies. In cells, this PMI modulation restricts the lateral mobility of K-Ras(G12C) and disrupts nanoclusters. The described strategy could be broadly applicable to selectively modulate transient PMIs.

DOI: https://doi.org/10.1021/acschembio.3c00413
Mol Cancer. 2023 Aug 18. 22(1): 138

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

Antonino Glaviano, Aaron S C Foo, Hiu Y Lam, Kenneth C H Yap, William Jacot, Robert H Jones, Huiyan Eng, Madhumathy G Nair, Pooyan Makvandi, Birgit Geoerger, Matthew H Kulke, Richard D Baird, Jyothi S Prabhu, Daniela Carbone, Camilla Pecoraro, Daniel B L Teh, Gautam Sethi, Vincenzo Cavalieri, Kevin H Lin, Nathalie R Javidi-Sharifi, Eneda Toska, Matthew S Davids, Jennifer R Brown, Patrizia Diana, Justin Stebbing, David A Fruman, Alan P Kumar.

  The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Keywords:  AKT inhibitors; ATP-competitive mTOR inhibitors; Allosteric mTOR inhibitors; Bi-steric mTOR inhibitors; Cancer; Dual PI3K/mTOR inhibitors; Isoform-specific PI3K inhibitors; PDK1 inhibitors; PI3K/AKT/mTORC pathway; Pan PI3K inhibitors

DOI:  https://doi.org/10.1186/s12943-023-01827-6
Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00559-2. [Epub ahead of print]83(16): 2832-2833

A sweet way to regulate cellular growth: OGT and mTOR join forces.

Pedro Latorre-Muro, Pere Puigserver.

In this issue, Xu and Pan et al1 report a glucose-sensing and activation mechanism of mTORC1 through the glycosyltransferase OGT, which activates Raptor, allowing lysosomal targeting of mTORC1 to promote cell proliferation.

DOI: https://doi.org/10.1016/j.molcel.2023.07.016
Curr Opin Struct Biol. 2023 Aug 10. pii: S0959-440X(23)00137-9. [Epub ahead of print]82 102663

Structural mechanisms of the mTOR pathway.

Karen Y Linde-Garelli, Kacper B Rogala.

The mTOR signaling pathway is essential for regulating cell growth and mammalian metabolism. The mTOR kinase forms two complexes, mTORC1 and mTORC2, which respond to external stimuli and regulate differential downstream targets. Cellular membrane-associated translocation mediates function and assembly of the mTOR complexes, and recent structural studies have begun uncovering the molecular basis by which the mTOR pathway (1) regulates signaling inputs, (2) recruits substrates, (3) localizes to biological membranes, and (4) becomes activated. Moreover, indications of dysregulated mTOR signaling are implicated in a wide range of diseases and an increasingly comprehensive understanding of structural mechanisms is driving novel translational development.

DOI: https://doi.org/10.1016/j.sbi.2023.102663
Proc Natl Acad Sci U S A. 2023 Aug 22. 120(34): e2304071120

Structural insights into the interaction of three Y-shaped ligands with PI3Kα.

Qingtong Zhou, Xiao Liu, Dario Neri, Wenxin Li, Nicholas Favalli, Gabriele Bassi, Su Yang, Dehua Yang, Peter K Vogt, Ming-Wei Wang.

  Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα.

Keywords:  binding pocket; chemical scaffold; drug target; ligand; phosphoinositide 3-kinase

DOI:  https://doi.org/10.1073/pnas.2304071120
Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00560-9. [Epub ahead of print]83(16): 3010-3026.e8

FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1.

Sungyun Cho, Yujin Chun, Long He, Cuauhtemoc B Ramirez, Kripa S Ganesh, Kyungjo Jeong, Junho Song, Jin Gyu Cheong, Zhongchi Li, Jungmin Choi, Joohwan Kim, Nikos Koundouros, Fangyuan Ding, Noah Dephoure, Cholsoon Jang, John Blenis, Gina Lee.

  The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and U1-70K-containing RNA-splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.

Keywords:  FAM120A; RNA splicing; RNA stability; SREBP; SRPK2; SRSF1; lipid metabolism; mTOR signaling

DOI:  https://doi.org/10.1016/j.molcel.2023.07.017
Trends Cancer. 2023 Aug 15. pii: S2405-8033(23)00137-1. [Epub ahead of print]

Next batter up! Targeting cancers with KRAS-G12D mutations.

Mara N Zeissig, Lauren M Ashwood, Olga Kondrashova, Kate D Sutherland.

  KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.

Keywords:  KRAS; KRAS G12D; MRTX1133; adenocarcinoma; tumor suppressor

DOI:  https://doi.org/10.1016/j.trecan.2023.07.010
Science. 2023 Aug 18. 381(6659): 794-799

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

Christopher J Schulze, Kyle J Seamon, Yulei Zhao, Yu C Yang, Jim Cregg, Dongsung Kim, Aidan Tomlinson, Tiffany J Choy, Zhican Wang, Ben Sang, Yasin Pourfarjam, Jessica Lucas, Antonio Cuevas-Navarro, Carlos Ayala-Santos, Alberto Vides, Chuanchuan Li, Abby Marquez, Mengqi Zhong, Vidyasiri Vemulapalli, Caroline Weller, Andrea Gould, Daniel M Whalen, Anthony Salvador, Anthony Milin, Mae Saldajeno-Concar, Nuntana Dinglasan, Anqi Chen, Jim Evans, John E Knox, Elena S Koltun, Mallika Singh, Robert Nichols, David Wildes, Adrian L Gill, Jacqueline A M Smith, Piro Lito.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

DOI: https://doi.org/10.1126/science.adg9652
Clin Cancer Res. 2023 Aug 15. pii: CCR-22-3655. [Epub ahead of print]

Facts and hopes on RAS inhibitors and cancer immunotherapy.

Jesse Boumelha, Miriam Molina-Arcas, Julian Downward.

While the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, there has been very little progress in combining immunotherapies with drugs that target oncogenic driver pathways. Some of the most important oncogenes in human cancer encode RAS family proteins; although these have proven challenging to target, recently drugs have been approved that inhibit a specific mutant form of KRAS, G12C. These have improved the treatment of lung cancer patients harboring this mutation but development of acquired drug resistance after initial responses has limited the impact on overall survival. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect anti-tumor immunity, and does so without compromising the critical role of normal RAS proteins in immune cells. This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some pre-clinical cancer models. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. A greater understanding of how oncogenic KRAS drives immune evasion and how mutant specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3655
EMBO J. 2023 Aug 14. e113987

PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer.

Konstantina Nikolatou, Emma Sandilands, Alvaro Román-Fernández, Erin M Cumming, Eva Freckmann, Sergio Lilla, Lori Buetow, Lynn McGarry, Matthew Neilson, Robin Shaw, David Strachan, Crispin Miller, Danny T Huang, Iain A McNeish, James C Norman, Sara Zanivan, David M Bryant.

  Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3 -rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.

Keywords:  3D spheroids; ARF6; Ovarian Cancer; PTEN; integrins

DOI:  https://doi.org/10.15252/embj.2023113987
Nat Commun. 2023 Aug 17. 14(1): 4998

One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids.

Maarten H Geurts, Shashank Gandhi, Matteo G Boretto, Ninouk Akkerman, Lucca L M Derks, Gijs van Son, Martina Celotti, Sarina Harshuk-Shabso, Flavia Peci, Harry Begthel, Delilah Hendriks, Paul Schürmann, Amanda Andersson-Rolf, Susana M Chuva de Sousa Lopes, Johan H van Es, Ruben van Boxtel, Hans Clevers.

Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show efficacy of cytosine and adenine base editors in modeling CTNNB1 hot-spot mutations in hepatocyte organoids. Next, we use C > T base editors to insert nonsense mutations in PTEN in endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug sensitivity assays on organoids harboring either PTEN or PTEN and PIK3CA mutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C > T and A > G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.

DOI: https://doi.org/10.1038/s41467-023-40701-3
Cell Commun Signal. 2023 Aug 18. 21(1): 209

NEK8 regulates colorectal cancer progression via phosphorylating MYC.

Beibei Cao, Kailun Zhang, Changjie Pan, Yifei Dong, Feng Lu.

  Radiotherapy and chemotherapy remain the mainstay of treatment for colorectal cancer (CRC), although their efficacy is limited. A detailed understanding of the molecular mechanisms underlying CRC progression could lead to the development of new therapeutic strategies. Although it has been established that MYC signaling is dysregulated in various human cancers, direct targeting MYC remains challenging due to its "undruggable" protein structure. Post-translational modification of proteins can affect their stability, activation, and subcellular localization. Hence, targeting the post-translational modification of MYC represents a promising approach to disrupting MYC signaling. Herein, we revealed that NEK8 positively regulates CRC progression by phosphorylating c-MYC protein at serine 405, which exhibited enhanced stability via polyubiquitination. Our findings shed light on the role of NEK8/MYC signaling in CRC progression, offering a novel and helpful target for colorectal cancer treatment. Video Abstract.

Keywords:  Colorectal cancer; MYC; NEK8

DOI:  https://doi.org/10.1186/s12964-023-01215-z
Cell. 2023 Aug 09. pii: S0092-8674(23)00781-X. [Epub ahead of print]

Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation.

Clinical Proteomic Tumor Analysis Consortium

  Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.

Keywords:  CPTAC; DNA damage response; genomics; mass spectrometry; metabolism; pan-cancer; post-translational modifications; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2023.07.013
Bioorg Chem. 2023 Aug 09. pii: S0045-2068(23)00440-6. [Epub ahead of print]140 106779

Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.

Chengbin Yang, Menghui Wang, Yimin Gong, Mingli Deng, Yun Ling, Qingquan Li, Jianxin Wang, Yaming Zhou.

  Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

Keywords:  Azaindole; Breast cancer; Cyclin-dependent kinase; PI3K inhibitors; Phosphatidylinositol 3-kinase

DOI:  https://doi.org/10.1016/j.bioorg.2023.106779
Oncogenesis. 2023 Aug 12. 12(1): 41

SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer.

Chunlin Lin, Penghang Lin, Huayan Lin, Hengxin Yao, Songyi Liu, Ruofan He, Hui Chen, Zuhong Teng, Robert M Hoffman, Jianxin Ye, Guangwei Zhu.

Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.

DOI: https://doi.org/10.1038/s41389-023-00488-w
Proc Natl Acad Sci U S A. 2023 Aug 22. 120(34): e2304184120

Evolutionary history of MEK1 illuminates the nature of deleterious mutations.

Ekaterina P Andrianova, Robert A Marmion, Stanislav Y Shvartsman, Igor B Zhulin.

  Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human MAP2K1 gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations in the MAP2K1 gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the cardiofaciocutaneous syndrome and arteriovenous malformation. Evaluating variants associated with a disease is a challenge, and computational genomic approaches aid in this process. Establishing evolutionary history of a gene improves computational prediction of disease-causing mutations; however, the evolutionary history of MEK1 is not well understood. Here, by revealing a precise evolutionary history of MEK1, we construct a well-defined dataset of MEK1 metazoan orthologs, which provides sufficient depth to distinguish between conserved and variable amino acid positions. We matched known and predicted disease-causing and benign mutations to evolutionary changes observed in corresponding amino acid positions and found that all known and many suspected disease-causing mutations are evolutionarily intolerable. We selected several variants that cannot be unambiguously assessed by automated prediction tools but that are confidently identified as "damaging" by our approach, for experimental validation in Drosophila. In all cases, evolutionary intolerant variants caused increased mortality and severe defects in fruit fly embryos confirming their damaging nature. We anticipate that our analysis will serve as a blueprint to help evaluate known and novel missense variants in MEK1 and that our approach will contribute to improving automated tools for disease-associated variant interpretation.

Keywords:  Drosophila; damaging mutations; serine–threonine kinase; variants of unknown significance

DOI:  https://doi.org/10.1073/pnas.2304184120