bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2021–06–06
thirteen papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research
  1. Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors.
  2. Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.
  3. Targeting BRAF and RAS in Colorectal Cancer.
  4. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
  5. The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction.
  6. Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells.
  7. mTOR Signaling in Metabolic Stress Adaptation.
  8. Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients.
  9. Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence.
  10. Tracing oncogene-driven remodelling of the intestinal stem cell niche.
  11. Vimentin loss promotes cancer proliferation through up-regulating Rictor/AKT/β-catenin signaling pathway.
  12. Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer.
  13. Rac1, A Potential Target for Tumor Therapy.
  1. Pharmaceutics. 2021 May 04. pii: 653. [Epub ahead of print]13(5):
    Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors.
    Alice Indini, Erika Rijavec, Michele Ghidini, Alessio Cortellini, Francesco Grossi.
      Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as "undruggable", largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind. However, this scenario has changed over the last years with the advent of novel KRAS inhibitors. In this review, we describe the role of KRAS mutation across different solid tumors, providing data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. A literature search was performed to select papers, abstracts, and oral presentation on KRAS inhibitory strategies in KRAS mutated solid tumors. Overall, the most promising therapeutic results have been obtained with molecules targeting KRAS G12C, thus paving the way for a significant therapeutic improvement in non-small cell lung cancer. Unfortunately, KRAS G12C mutation is rather uncommon in other solid tumors, namely pancreatic ductal adenocarcinoma and colorectal cancer. Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.
    Keywords:  AMG510; KRAS; LGSOC; NSCLC; colorectal cancer; endometrial cancer; pancreatic cancer; sotorasib
    DOI:  https://doi.org/10.3390/pharmaceutics13050653
  2. J Natl Cancer Inst. 2021 Jun 01. pii: djab112. [Epub ahead of print]
    Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.
    Jun Yin, Romain Cohen, Zhaohui Jin, Heshan Liu, Levi Pederson, Richard Adams, Axel Grothey, Timothy S Maughan, Alan Venook, Eric Van Cutsem, Cornelis Punt, Miriam Koopman, Alfredo Falcone, Niall C Tebbutt, Matthew T Seymour, Carsten Bokemeyer, Eduardo Diaz Rubio, Richard Kaplan, Volker Heinemann, Benoist Chibaudel, Takayuki Yoshino, John Zalcberg, Thierry Andre, Aimery De Gramont, Qian Shi, Heinz-Josef Lenz.
       BACKGROUND: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.
    METHODS: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided.
    RESULTS: Compared to right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness.
    CONCLUSIONS: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
    DOI:  https://doi.org/10.1093/jnci/djab112
  3. Cancers (Basel). 2021 May 03. pii: 2201. [Epub ahead of print]13(9):
    Targeting BRAF and RAS in Colorectal Cancer.
    Helene Bellio, Jean David Fumet, Francois Ghiringhelli.
      Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination.
    Keywords:  BRAF; KRAS; colorectal cancer; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13092201
  4. Nature. 2021 Jun 02.
    NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
    Dustin J Flanagan, Nalle Pentinmikko, Kalle Luopajärvi, Nicky J Willis, Kathryn Gilroy, Alexander P Raven, Lynn Mcgarry, Johanna I Englund, Anna T Webb, Sandra Scharaw, Nadia Nasreddin, Michael C Hodder, Rachel A Ridgway, Emma Minnee, Nathalie Sphyris, Ella Gilchrist, Arafath K Najumudeen, Beatrice Romagnolo, Christine Perret, Ann C Williams, Hans Clevers, Pirjo Nummela, Marianne Lähde, Kari Alitalo, Ville Hietakangas, Ann Hedley, William Clark, Colin Nixon, Kristina Kirschner, E Yvonne Jones, Ari Ristimäki, Simon J Leedham, Paul V Fish, Jean-Paul Vincent, Pekka Katajisto, Owen J Sansom.
      The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
    DOI:  https://doi.org/10.1038/s41586-021-03525-z
  5. Genes (Basel). 2021 May 27. pii: 819. [Epub ahead of print]12(6):
    The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction.
    Olga Soriano, Marta Alcón-Pérez, Miguel Vicente-Manzanares, Esther Castellano.
      Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.
    Keywords:  Ras; Rho; myosin II
    DOI:  https://doi.org/10.3390/genes12060819
  6. Cancers (Basel). 2021 May 16. pii: 2405. [Epub ahead of print]13(10):
    Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells.
    Suree Kim, Sukyeong Heo, Joseph Brzostowski, Dongmin Kang.
      The serine/threonine kinase AKT is a major effector during phosphatidylinositol 3-kinase (PI3K)-driven cell signal transduction in response to extracellular stimuli. AKT activation mechanisms have been extensively studied; however, the mechanism underlying target of rapamycin complex 2 (mTORC2) phosphorylation of AKT at Ser473 in the cellular endomembrane system remains to be elucidated. Here, we demonstrate that endocytosis is required for AKT activation through phosphorylation at Ser473 via mTORC2 using platelet-derived growth factor-stimulated U87MG glioma cells. mTORC2 components are localized to early endosomes during growth factor activation, and the association of mTORC2 with early endosomes is responsible for the local activation of AKT, which is critical for specific signal transduction through glycogen synthase kinase-3 beta and forkhead box O1/O3 phosphorylation. Furthermore, endosomal phosphoinositide, represented by PtdIns(3,4)P2, provides a binding platform for mTORC2 to phosphorylate AKT Ser473 in endosomes through mammalian Sty1/Spc1-interacting protein (mSIN), a pleckstrin homology domain-containing protein, and is dispensable for AKT phosphorylation at Thr308. This PtdIns(3,4)P2-mediated endosomal AKT activation provides a means to integrate PI3K activated by diverse stimuli to mTORC2 assembly. These early endosomal events induced by endocytosis, together with the previously identified AKT activation by PtdIns(3,4,5)P3, contribute to the strengthening of the transduction of AKT signaling through phosphoinositide.
    Keywords:  AKT; endocytosis; endosome; mTORC2; phosphatidylinositol
    DOI:  https://doi.org/10.3390/cancers13102405
  7. Biomolecules. 2021 May 01. pii: 681. [Epub ahead of print]11(5):
    mTOR Signaling in Metabolic Stress Adaptation.
    Cheng-Wei Wu, Kenneth B Storey.
      The mechanistic target of rapamycin (mTOR) is a central regulator of cellular homeostasis that integrates environmental and nutrient signals to control cell growth and survival. Over the past two decades, extensive studies of mTOR have implicated the importance of this protein complex in regulating a broad range of metabolic functions, as well as its role in the progression of various human diseases. Recently, mTOR has emerged as a key signaling molecule in regulating animal entry into a hypometabolic state as a survival strategy in response to environmental stress. Here, we review current knowledge of the role that mTOR plays in contributing to natural hypometabolic states such as hibernation, estivation, hypoxia/anoxia tolerance, and dauer diapause. Studies across a diverse range of animal species reveal that mTOR exhibits unique regulatory patterns in an environmental stressor-dependent manner. We discuss how key signaling proteins within the mTOR signaling pathways are regulated in different animal models of stress, and describe how each of these regulations uniquely contribute to promoting animal survival in a hypometabolic state.
    Keywords:  Akt; TOR; anoxia; cell signaling; dauer; environmental stress; estivation; hibernation; hypoxia; metabolism; protein translation
    DOI:  https://doi.org/10.3390/biom11050681
  8. Int J Mol Sci. 2021 May 09. pii: 5019. [Epub ahead of print]22(9):
    Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients.
    Helena Oliveres, David Pesántez, Joan Maurel.
      Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.
    Keywords:  insulin-like growth factor receptor; metastatic colorectal cancer
    DOI:  https://doi.org/10.3390/ijms22095019
  9. Sci Signal. 2021 Jun 01. pii: eaaz3578. [Epub ahead of print]14(685):
    Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence.
    Takao Ito, Tatsushi Igaki.
      The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam bantam-mediated repression of the E3 ligase-associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.
    DOI:  https://doi.org/10.1126/scisignal.aaz3578
  10. Nature. 2021 Jun 02.
    Tracing oncogene-driven remodelling of the intestinal stem cell niche.
    Min Kyu Yum, Seungmin Han, Juergen Fink, Szu-Hsien Sam Wu, Catherine Dabrowska, Teodora Trendafilova, Roxana Mustata, Lemonia Chatzeli, Roberta Azzarelli, Irina Pshenichnaya, Eunmin Lee, Frances England, Jong Kyoung Kim, Daniel E Stange, Anna Philpott, Joo-Hyeon Lee, Bon-Kyoung Koo, Benjamin D Simons.
      Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.
    DOI:  https://doi.org/10.1038/s41586-021-03605-0
  11. Exp Cell Res. 2021 May 27. pii: S0014-4827(21)00198-1. [Epub ahead of print] 112666
    Vimentin loss promotes cancer proliferation through up-regulating Rictor/AKT/β-catenin signaling pathway.
    Youxiang Ding, Conggai Lv, You Zhou, Heng Zhang, Li Zhao, Yuting Xu, Xiangshan Fan.
      Vimentin protein is one of the main cytoskeleton and plays an important role in cell motility and metastasis. Nowadays, vimentin is widely studied as an epithelial-mesenchymal transition (EMT) marker of cancer cells while its involvement in cancer proliferation is poorly understood. In this study, we investigated the participation of vimentin in regulating cancer proliferation by silencing VIM gene in four cancer cell lines. Our results demonstrated that vimentin loss significantly induced cancer cell proliferation both in vitro and in vivo, which has not been reported so far. Mechanistically, knockdown of vimentin expression activated AKT phosphorylation and its downstream β-catenin signaling. Nuclear translocation and transcriptional activity of β-catenin was enhanced after silencing vimentin expression. Furthermore, vimentin loss could prevent Rictor from autophagy-dependent degradation via reducing AMPK-mediated autophagy signaling. AICAR, an AMPK activator, down-regulated Rictor and p-AKT levels while vimentin knockdown could rescue the effects. In vivo, it was also found that Ki67 expression and p-AKT/β-catenin signaling pathway were obviously up-regulated in the tumor tissues in which vimentin was silenced compared to control groups. Taken together, these data showed the novel function of vimentin in regulating cancer proliferation via Rictor/AKT/β-catenin signaling pathway, which suggested that it need more careful consideration before inhibiting metastatic cancers through targeting vimentin.
    Keywords:  Rictor/mTORC2; Vimentin; autophagy; cell proliferation; β-catenin
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112666
  12. Mol Biol Rep. 2021 May 31.
    Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer.
    Zeinab Moafian, Abolfazl Maghrouni, Arash Soltani, Seyed Isaac Hashemy.
      Colorectal cancer (CRC) is the third commonest cancer globally, with metastasis being the reason for cancer-associated mortality. Much is still unknown biochemically about CRC, and with current treatments that are not wholly effective over time, new therapeutics are urgently needed. Emerging evidence has shown the importance of non-coding RNAs such as lncRNAs and miRNAs functions in the development and progression of CRC. However, the exact underlying mechanism of these types of RNAs in CRC is still mostly unknown. PI3K/AKT/mTOR pathway contributes to many cellular processes, and dysregulation of this pathway frequently occurs in cancers. In this review, the authors have mostly focused on the significant non-coding RNAs regulators of the PI3K/AKT/mTOR pathway and their contribution to the development or inhibition of CRC and their potential as diagnostic or therapeutic targets in CRC treatment.
    Keywords:  AKT; Colorectal cancer (CRC); LncRNAs; MicroRNAs; PI3K; mTOR pathway
    DOI:  https://doi.org/10.1007/s11033-021-06458-y
  13. Front Oncol. 2021 ;11 674426
    Rac1, A Potential Target for Tumor Therapy.
    Jiaxin Liang, Linda Oyang, Shan Rao, Yaqian Han, Xia Luo, Pin Yi, Jinguan Lin, Longzheng Xia, Jiaqi Hu, Shiming Tan, Lu Tang, Qing Pan, Yanyan Tang, Yujuan Zhou, Qianjin Liao.
      RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.
    Keywords:  Rac1; cancer stemness; metastasis; therapy resistance; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2021.674426
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