bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022‒11‒27
seventeen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
  1. The mutational profiles and corresponding therapeutic implications of PI3K mutations in cancer.
  2. Glucocorticoid receptor and RAS: an unexpected couple in cancer.
  3. Co-targeting KRAS G12C and EGFR reduces both mutant and wild-type RAS-GTP.
  4. Glimmers of hope for targeting oncogenic KRAS-G12D.
  5. Dysregulated amino acid sensing drives colorectal cancer growth and metabolic reprogramming leading to chemoresistance.
  6. Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R.
  7. Targeting PTEN Regulation by Post Translational Modifications.
  8. Regulation of EGF-stimulated activation of the PI-3K/AKT pathway by exocyst-mediated exocytosis.
  9. PI(4,5)P2 diffuses freely in the plasma membrane even within high-density effector protein complexes.
  10. Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy.
  11. SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer.
  12. Path Sampling Simulations Reveal How the Q61L Mutation Alters the Dynamics of KRas.
  13. GSK-3β phosphorylation of DHX33 leads to its ubiquitination mediated protein degradation.
  14. Structural basis of tankyrase activation by polymerization.
  15. MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors.
  16. MYC multimers shield stalled replication forks from RNA polymerase.
  17. Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial.
  1. Adv Biol Regul. 2022 Nov 15. pii: S2212-4926(22)00074-4. [Epub ahead of print] 100934
    The mutational profiles and corresponding therapeutic implications of PI3K mutations in cancer.
    Nathan K VanLandingham, Andrew Nazarenko, Jennifer R Grandis, Daniel E Johnson.
      Genetic alterations of the PIK3CA gene, encoding the p110α catalytic subunit of PI3Kα enzyme, are found in a broad spectrum of human cancers. Many cancer-associated PIK3CA mutations occur at 3 hotspot locations and are termed canonical mutations. Canonical mutations result in hyperactivation of PI3K and promote oncogenesis via the PI3K/AKT/mTOR and PI3K/COX-2/PGE2 signaling pathways. These mutations also may serve as predictive biomarkers of response to PI3K inhibitors, as well as NSAID therapy. A large number of non-canonical PIK3CA mutations have also been identified in human tumors, but their functional properties are poorly understood. Here we review the landscape of PIK3CA mutations in different cancers and efforts underway to define the functional properties of non-canonical PIK3CA mutations. In addition, we summarize what has been learned from clinical trials of PI3K inhibitors as well as current trials incorporating these molecular targeting agents.
    Keywords:  Alpelisib; PIK3CA; Phosphoinositide 3-kinase alpha; p110alpha
    DOI:  https://doi.org/10.1016/j.jbior.2022.100934
  2. Trends Cell Biol. 2022 Nov 22. pii: S0962-8924(22)00253-7. [Epub ahead of print]
    Glucocorticoid receptor and RAS: an unexpected couple in cancer.
    Ion C Cirstea, Herwig P Moll, Jan Tuckermann.
      Constitutively activated rat sarcoma (RAS) GTPases are one of the major drivers of tumor growth and are difficult drug targets. The glucocorticoid receptor (GR), a nuclear receptor primarily acting in the nucleus, is a potent modulator of inflammation and regulator of metabolism and cell growth. Emerging evidence has revealed that GR modulates RAS-dependent signaling and RAS activation. The unliganded GR decreases RAS activation, and, upon ligand binding, GR leaves RAS complexes, is translocated into the nucleus, and unleashes the activation of RAS and its downstream pathways. GR forms a complex with RAS and RAF1 and their associated proteins, such as members of the 14-3-3 family of adapter proteins. The exploration of RAS-GR complex formation and maintenance will help to develop much-needed breakthroughs in oncogenic RAS biology and thus help to alleviate tumor growth and burden.
    Keywords:  Ras GTPases; cytoplasmic action; glucocorticoid receptor; tumor growth
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.002
  3. NPJ Precis Oncol. 2022 Nov 23. 6(1): 86
    Co-targeting KRAS G12C and EGFR reduces both mutant and wild-type RAS-GTP.
    Thomas McFall, Michael Trogdon, Anita C Guizar, John F Langenheim, Laura Sisk-Hackworth, Edward C Stites.
      The combination of KRAS G12C inhibitors with EGFR inhibitors has reproducibly been shown to be beneficial. Here, we identify another benefit of this combination: it effectively inhibits both wild-type and mutant RAS. We believe that targeting both mutant and wild-type RAS helps explain why this combination of inhibitors is effective.
    DOI:  https://doi.org/10.1038/s41698-022-00329-w
  4. Cancer Gene Ther. 2022 Nov 21.
    Glimmers of hope for targeting oncogenic KRAS-G12D.
    Daolin Tang, Rui Kang.
      KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers. Strategies targeting the oncogenic KRAS pathway include direct and indirect approaches. KRAS-G12C inhibitors developed based on binding to the switch II pocket structure of KRAS mutant protein represent a breakthrough in the development of targeted therapeutic strategies against oncogenic proteins previously considered undruggable. The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Emerging research shows that other host point mutations in KRAS can also be directly targeted by small-molecule compounds. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor.
    DOI:  https://doi.org/10.1038/s41417-022-00561-3
  5. Gastroenterology. 2022 Nov 15. pii: S0016-5085(22)01273-2. [Epub ahead of print]
    Dysregulated amino acid sensing drives colorectal cancer growth and metabolic reprogramming leading to chemoresistance.
    Sumeet Solanki, Katherine Sanchez, Varun Ponnusamy, Vasudha Kota, Hannah N Bell, Chun-Seok Cho, Allison H Kowalsky, Michael Green, Jun Hee Lee, Yatrik M Shah.
      BACKGROUND AND AIMS: CRC is a devastating disease highly modulated by dietary nutrients. mTORC1 contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity following therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid sensing GTPase activity towards Rags complexes (GATOR). The role of amino acid sensing pathways in CRC is unclear.METHODS: Human colon cancer cell lines, preclinical intestinal epithelial specific GATOR1 and GATOR2 knockout mouse subjected to colitis induced or sporadic colon tumor models, siRNA screening targeting regulators of mTORC1, and CRC patient tissues were used to assess the role of amino acid sensing in CRC.
    RESULTS: We identified loss-of-function mutations of the GATOR1 complex in CRC and show that altered expression of amino acid sensing pathways predict poor patient outcomes. We show that dysregulated amino acid sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic resistant colon cancer patients exhibited deregulated amino acid sensing. Limiting amino acids in in vitro and in vivo model (low protein diet) reverted drug resistance revealing a metabolic vulnerability.
    CONCLUSIONS: Our findings suggest a critical role of amino acid sensing pathways in driving CRC and highlights translational implications of dietary protein intervention in CRC.
    Keywords:  5-Fluorouracil; Depdc5; Sestrin 2; Wdr24; mTORC1
    DOI:  https://doi.org/10.1053/j.gastro.2022.11.014
  6. Acta Pharmacol Sin. 2022 Nov 21.
    Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R.
    Wei-Liang Qi, Hui-Yu Li, Yi Wang, Lan Xu, Jie-Ting Deng, Xi Zhang, Yu-Xiang Wang, Ling-Hua Meng.
      Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.
    Keywords:  AMG510; KRasG12C; PI3K; combination therapy; drug resistance
    DOI:  https://doi.org/10.1038/s41401-022-01015-0
  7. Cancers (Basel). 2022 Nov 15. pii: 5613. [Epub ahead of print]14(22):
    Targeting PTEN Regulation by Post Translational Modifications.
    Ana González-García, Antonio Garrido, Ana C Carrera.
      Phosphatidylinositol-3,4,5-triphosphate (PIP3) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP3 levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP3 is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP3 levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP3 dephosphorylation to PIP2. PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors.
    Keywords:  PTEN; phosphorylation; post-translational modification; sumoylation; ubiquitination
    DOI:  https://doi.org/10.3390/cancers14225613
  8. Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2208947119
    Regulation of EGF-stimulated activation of the PI-3K/AKT pathway by exocyst-mediated exocytosis.
    Seong J An, Alexander Anneken, Zhiqun Xi, Changseon Choi, Joseph Schlessinger, Derek Toomre.
      The phosphoinositide-3 kinase (PI-3K)/AKT cell survival pathway is an important pathway activated by EGFR signaling. Here we show, that in addition to previously described critical components of this pathway, i.e., the docking protein Gab1, the PI-3K/AKT pathway in epithelial cells is regulated by the exocyst complex, which is a vesicle tether that is essential for exocytosis. Using live-cell imaging, we demonstrate that PI(3,4,5)P3 levels fluctuate at the membrane on a minutes time scale and that these fluctuations are associated with local PI(3,4,5)P3 increases at sites where recycling vesicles undergo exocytic fusion. Supporting a role for exocytosis in PI(3,4,5)P3 generation, acute promotion of exocytosis by optogenetically driving exocyst-mediated vesicle tethering up-regulates PI(3,4,5)P3 production and AKT activation. Conversely, acute inhibition of exocytosis using Endosidin2, a small-molecule inhibitor of the exocyst subunit Exo70 (also designated EXOC7), or inhibition of exocyst function by siRNA-mediated knockdown of the exocyst subunit Sec15 (EXOC6), impairs PI(3,4,5)P3 production and AKT activation induced by EGF stimulation of epithelial cells. Moreover, prolonged inhibition of EGF signaling by EGFR tyrosine kinase inhibitors results in spontaneous reactivation of AKT without a concomitant relief of EGFR inhibition. However, this reactivation can be negated by acutely inhibiting the exocyst. These experiments demonstrate that exocyst-mediated exocytosis-by regulating PI(3,4,5)P3 levels at the plasma membrane-subserves activation of the PI-3K/AKT pathway by EGFR in epithelial cells.
    Keywords:  biochemistry; biological sciences; cell biology
    DOI:  https://doi.org/10.1073/pnas.2208947119
  9. J Cell Biol. 2023 Feb 06. pii: e202204099. [Epub ahead of print]222(2):
    PI(4,5)P2 diffuses freely in the plasma membrane even within high-density effector protein complexes.
    Jonathan Pacheco, Anna C Cassidy, James P Zewe, Rachel C Wills, Gerald R V Hammond.
      The lipid phosphatidyl-D-myo-inositol-4,5-bisphosphate [PI(4,5)P2] is a master regulator of plasma membrane (PM) function. Its effector proteins regulate transport, signaling, and cytoskeletal processes that define PM structure and function. How a single type of lipid regulates so many parallel processes is unclear. We tested the hypothesis that spatially separate PI(4,5)P2 pools associate with different PM complexes. The mobility of PI(4,5)P2 was measured using biosensors by single-particle tracking. We found that PM lipids including PI(4,5)P2 diffuse rapidly (∼0.3 µm2/s) with Brownian motion, although they spend one third of their time diffusing more slowly. Surprisingly, areas of the PM occupied by PI(4,5)P2-dependent complexes did not slow PI(4,5)P2 lateral mobility. Only the spectrin and septin cytoskeletons showed reduced PI(4,5)P2 diffusion. We conclude that even structures with high densities of PI(4,5)P2 effector proteins, such as clathrin-coated pits and focal adhesions, do not corral unbound PI(4,5)P2, questioning a role for spatially segregated PI(4,5)P2 pools in organizing and regulating PM functions.
    DOI:  https://doi.org/10.1083/jcb.202204099
  10. Cancers (Basel). 2022 Nov 10. pii: 5520. [Epub ahead of print]14(22):
    Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy.
    Abdelhakim Bouyahya, Aicha El Allam, Sara Aboulaghras, Saad Bakrim, Naoual El Menyiy, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Taoufiq Benali, Learn-Han Lee, Nasreddine El Omari, Khang Wen Goh, Long Chiau Ming, Mohammad S Mubarak.
      The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine-protein kinase, which regulates many biological processes related to metabolism, cancer, immune function, and aging. It is an essential protein kinase that belongs to the phosphoinositide-3-kinase (PI3K) family and has two known signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Even though mTOR signaling plays a critical role in promoting mitochondria-related protein synthesis, suppressing the catabolic process of autophagy, contributing to lipid metabolism, engaging in ribosome formation, and acting as a critical regulator of mRNA translation, it remains one of the significant signaling systems involved in the tumor process, particularly in apoptosis, cell cycle, and cancer cell proliferation. Therefore, the mTOR signaling system could be suggested as a cancer biomarker, and its targeting is important in anti-tumor therapy research. Indeed, its dysregulation is involved in different types of cancers such as colon, neck, cervical, head, lung, breast, reproductive, and bone cancers, as well as nasopharyngeal carcinoma. Moreover, recent investigations showed that targeting mTOR could be considered as cancer therapy. Accordingly, this review presents an overview of recent developments associated with the mTOR signaling pathway and its molecular involvement in various human cancer types. It also summarizes the research progress of different mTOR inhibitors, including natural and synthetised compounds and their main mechanisms, as well as the rational combinations with immunotherapies.
    Keywords:  cancer; immunotherapy; mTOR; mTOR inhibitors; natural drugs
    DOI:  https://doi.org/10.3390/cancers14225520
  11. J Biol Chem. 2022 Nov 21. pii: S0021-9258(22)01178-4. [Epub ahead of print] 102735
    SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer.
    Aravinda-Bharathi Ramakrishnan, Peter E Burby, Kavya Adiga, Ken M Cadigan.
      Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes by down-regulating β-catenin protein levels. Here, we find using colony formation and cell growth assays that SOX9 surprisingly promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. In contrast to how it indirectly represses Wnt targets, SOX9 directly co-occupies and activates multiple Wnt-responsive enhancers in CRC cells. Our examination of the binding site grammar of these enhancers shows the presence of TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with the presence or absence of SOX9 binding sites on Wnt-regulated enhancers determining whether they are directly activated or indirectly repressed by SOX9.
    Keywords:  Wnt pathway; Wnt signaling; colorectal cancer; enhancers; gene transcription; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2022.102735
  12. J Phys Chem B. 2022 Nov 25.
    Path Sampling Simulations Reveal How the Q61L Mutation Alters the Dynamics of KRas.
    Sander Roet, Ferry Hooft, Peter G Bolhuis, David W H Swenson, Jocelyne Vreede.
      Flexibility is essential for many proteins to function, but can be difficult to characterize. Experiments lack resolution in space and time, while the time scales involved are prohibitively long for straightforward molecular dynamics simulations. In this work, we present a multiple state transition path sampling simulation study of a protein that has been notoriously difficult to characterize in its active state. The GTPase enzyme KRas is a signal transduction protein in pathways for cell differentiation, growth, and division. When active, KRas tightly binds guanosine triphosphate (GTP) in a rigid state. The protein-GTP complex can also visit more flexible states, in which it is not active. KRas mutations can affect the conversion between these rigid and flexible states, thus prolonging the activation of signal transduction pathways, which may result in tumor formation. In this work, we apply path sampling simulations to investigate the dynamic behavior of KRas-4B (wild type, WT) and the oncogenic mutant Q61L (Q61L). Our results show that KRas visits several conformational states, which are the same for WT and Q61L. The multiple state transition path sampling (MSTPS) method samples transitions between the different states in a single calculation. Tracking which transitions occur shows large differences between WT and Q61L. The MSTPS results further reveal that for Q61L, a route to a more flexible state is inaccessible, thus shifting the equilibrium to more rigid states. The methodology presented here enables a detailed characterization of protein flexibility on time scales not accessible with brute-force molecular dynamics simulations.
    DOI:  https://doi.org/10.1021/acs.jpcb.2c06235
  13. Cell Signal. 2022 Nov 17. pii: S0898-6568(22)00288-1. [Epub ahead of print] 110526
    GSK-3β phosphorylation of DHX33 leads to its ubiquitination mediated protein degradation.
    Yandong Zhang, Shiyun Chen, Cheng Peng.
      DHX33 is a member of DEAD/H box protein family, and is involved in both RNA and DNA metabolism. It plays diverse roles in multiple cellular activities. DHX33 overexpression has been found to promote the development of many human cancers. However, the underlying mechanism to explain its high expression in cancer cells remains incompletely resolved. In this study, with both human cancer cell lines and normal fibroblasts, we found glycogen synthase kinase 3β (GSK-3β) regulates DHX33 protein stability. This is through its direct phosphorylation of DHX33 on T482, which triggers ubiquitination mediate protein degradation. We further identified one of the major ubiquitination sites of DHX33 to be on its N-terminal K94, a critical residue previously found to be important and highly conserved for ATP binding and helicase activity. Our study for the first time reveals an important upstream regulator, GSK-3β, as a critical kinase to phosphorylate DHX33 at the post-translational level leading to its degradation. Moreover, cancer cells have frequent GSK3β deactivation to disrupt this signaling cascade. Therefore, DHX33 is stabilized in many cancer cells as compared to normal cells. Our study unveils an important post-translational regulation of DHX33 in cells and further unveils a novel mechanism for DHX33 overexpression in cancer cells.
    Keywords:  DHX33; GSK-3β; Protein degradation; RNA helicase; Ubiquitination
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110526
  14. Nature. 2022 Nov 23.
    Structural basis of tankyrase activation by polymerization.
    Nisha Pillay, Laura Mariotti, Mariola Zaleska, Oviya Inian, Matthew Jessop, Sam Hibbs, Ambroise Desfosses, Paul C R Hopkins, Catherine M Templeton, Fabienne Beuron, Edward P Morris, Sebastian Guettler.
      The poly-ADP-ribosyltransferase tankyrase (TNKS, TNKS2) controls a wide range of disease-relevant cellular processes, including WNT-β-catenin signalling, telomere length maintenance, Hippo signalling, DNA damage repair and glucose homeostasis1,2. This has incentivized the development of tankyrase inhibitors. Notwithstanding, our knowledge of the mechanisms that control tankyrase activity has remained limited. Both catalytic and non-catalytic functions of tankyrase depend on its filamentous polymerization3-5. Here we report the cryo-electron microscopy reconstruction of a filament formed by a minimal active unit of tankyrase, comprising the polymerizing sterile alpha motif (SAM) domain and its adjacent catalytic domain. The SAM domain forms a novel antiparallel double helix, positioning the protruding catalytic domains for recurring head-to-head and tail-to-tail interactions. The head interactions are highly conserved among tankyrases and induce an allosteric switch in the active site within the catalytic domain to promote catalysis. Although the tail interactions have a limited effect on catalysis, they are essential to tankyrase function in WNT-β-catenin signalling. This work reveals a novel SAM domain polymerization mode, illustrates how supramolecular assembly controls catalytic and non-catalytic functions, provides important structural insights into the regulation of a non-DNA-dependent poly-ADP-ribosyltransferase and will guide future efforts to modulate tankyrase and decipher its contribution to disease mechanisms.
    DOI:  https://doi.org/10.1038/s41586-022-05449-8
  15. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01578-9. [Epub ahead of print]41(8): 111704
    MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors.
    Laura Urbanski, Mattia Brugiolo, SungHee Park, Brittany L Angarola, Nathan K Leclair, Marina Yurieva, Phil Palmer, Sangram Keshari Sahu, Olga Anczuków.
      MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors.
    Keywords:  CP: Cancer; MYC; RNA splicing; SR proteins; alternative splicing; breast cancer; cancer; co-expression analysis; co-expression modules; oncogenes; organoids; pan-cancer; splicing factors
    DOI:  https://doi.org/10.1016/j.celrep.2022.111704
  16. Nature. 2022 Nov 23.
    MYC multimers shield stalled replication forks from RNA polymerase.
    Daniel Solvie, Apoorva Baluapuri, Leonie Uhl, Daniel Fleischhauer, Theresa Endres, Dimitrios Papadopoulos, Amel Aziba, Abdallah Gaballa, Ivan Mikicic, Ekaterina Isaakova, Celeste Giansanti, Jennifer Jansen, Marvin Jungblut, Teresa Klein, Christina Schülein-Völk, Hans Maric, Sören Doose, Markus Sauer, Petra Beli, Andreas Rosenwald, Matthias Dobbelstein, Elmar Wolf, Martin Eilers.
      Oncoproteins of the MYC family drive the development of numerous human tumours1. In unperturbed cells, MYC proteins bind to nearly all active promoters and control transcription by RNA polymerase II2,3. MYC proteins can also coordinate transcription with DNA replication4,5 and promote the repair of transcription-associated DNA damage6, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks7,8. MYC multimerization is triggered in a HUWE16 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double strand break formation during S-phase, suggesting that the multimerization of MYC enables tumour cells to proliferate under stressful conditions.
    DOI:  https://doi.org/10.1038/s41586-022-05469-4
  17. BMJ Open. 2022 11 21. 12(11): e063700
    Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial.
    Jean-Baptiste Trouiller, Bérengère Macabeo, Andrew Poll, Dan Howard, Andy Buckland, Marine Sivignon, Emilie Clay, David Malka, Emmanuelle Samalin, Mondher Toumi, Philippe Laramée.
      OBJECTIVE: The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system.DESIGN: A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values.
    OUTCOME MEASURES: The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted.
    RESULTS: The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively.
    CONCLUSIONS: This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.
    Keywords:  Adult oncology; Gastrointestinal tumours; HEALTH ECONOMICS
    DOI:  https://doi.org/10.1136/bmjopen-2022-063700
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