bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022–01–09
thirteen papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research
  1. Recent clinical advances in PI3K inhibitors on colorectal cancer.
  2. Sotorasib's Benefits in Colorectal Cancer Modest.
  3. Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.
  4. Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.
  5. Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.
  6. Biochemical characterization of the interaction between KRAS and Argonaute 2.
  7. PIP3 abundance overcomes PI3K signaling selectivity in invadopodia.
  8. Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives.
  9. Photosynthetic assimilation of CO2 regulates TOR activity.
  10. Monitoring of RAS mutant clones in plasma of patients with RAS mutant metastatic colorectal cancer.
  11. Enteric glia bring fresh WNT to the intestinal stem cell niche.
  12. Analysis of KRAS Mutation Status Prediction Model for Colorectal Cancer Based on Medical Imaging.
  13. The functions and roles of sestrins in regulating human diseases.
  1. Pharmazie. 2021 Dec 05. 76(12): 568-573
    Recent clinical advances in PI3K inhibitors on colorectal cancer.
    Mingliang Zhu, Qiuyang Jin, Yizhou Xin.
      The PI3K/Akt/mTOR signaling pathway has the functions of regulating cell cycle, participating in tumor angiogenesis, affecting tumor invasion activity and metastasis, regulating apoptosis and autophagy, and participating in tumor drug resistance. Alpelisib (a PI3K inhibitor) has now been approved by the FDA for the treatment of PIK3CA mutant HR-positive/HER2-negative advanced/metastatic breast cancer in combination with fulvestrant which is the first PI3K inhibitor approved for breast cancer treatment. In some human colorectal cancer cells, the activation of this signal pathway is excessive and the negative regulation is impaired. Inhibitors targeting PI3K, a key protein in the PI3K/Akt/mTOR signaling pathway, have a positive effect on the treatment of colorectal cancer. Based on the role of PI3K/Akt/mTOR in the occurrence and development of colorectal cancer and its clinical application, this article reviews the PI3K inhibitors that have been on the market or are in clinical trials.
    DOI:  https://doi.org/10.1691/ph.2021.1820
  2. Cancer Discov. 2022 Jan 05.
    Sotorasib's Benefits in Colorectal Cancer Modest.
      The KRAS inhibitor sotorasib provides some clinical benefit in patients with advanced or metastatic KRASG12C-mutant colorectal cancer, according to results of a phase II clinical trial. The objective response rate was 9.7%, the disease control rate was 82.3%, and the progression-free survival was 4 months.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2022-0001
  3. J Clin Invest. 2022 Jan 06. pii: e155523. [Epub ahead of print]
    Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.
    Yihsuan S Tsai, Mark G Woodcock, Salma H Azam, Leigh B Thorne, Krishna L Kanchi, Joel S Parker, Benjamin G Vincent, Chad V Pecot.
      The KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance. Here, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep RNA and whole exome sequencing comparing pre-treatment, post-treatment and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition. In addition to decreased KRAS G12C mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation and tumor angiogenesis, and several lines of evidence of immunologic evasion. Together, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling and diverse remodeling of the tumor microenvironment.
    Keywords:  Adaptive immunity; Drug therapy; Genetics; Molecular genetics; Oncology
    DOI:  https://doi.org/10.1172/JCI155523
  4. Adv Biol Regul. 2021 Dec 06. pii: S2212-4926(21)00072-5. [Epub ahead of print] 100854
    Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.
    Meena Jhanwar-Uniyal, Jose F Dominguez, Avinash L Mohan, Michael E Tobias, Chirag D Gandhi.
      Aberrant signaling of mechanistic target of rapamycin (mTOR' aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). Glioblastoma mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. There complexes are named mTORC1 and mTORC2 and downstream activated substrate execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and it's analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin2 caused a concentration dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E-BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell proliferation and migration. Torin1 showed similar effects only at higher doses. Another small molecule compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. Torin1 suppressed phosphorylation of PRAS40Thr246, however Torin2 completely abolished it. XL388 treatment inhibited the phosphorylation of PRAS40Thr246 at higher doses only. These findings underscore the use of novel compounds in treatment of cancer. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways.
    Keywords:  Glioblastoma; mTOR; mTORC1 mTORC2
    DOI:  https://doi.org/10.1016/j.jbior.2021.100854
  5. Proc Natl Acad Sci U S A. 2022 Jan 04. pii: e2113297119. [Epub ahead of print]119(1):
    Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.
    Helgi I Ingólfsson, Chris Neale, Timothy S Carpenter, Rebika Shrestha, Cesar A López, Timothy H Tran, Tomas Oppelstrup, Harsh Bhatia, Liam G Stanton, Xiaohua Zhang, Shiv Sundram, Francesco Di Natale, Animesh Agarwal, Gautham Dharuman, Sara I L Kokkila Schumacher, Thomas Turbyville, Gulcin Gulten, Que N Van, Debanjan Goswami, Frantz Jean-Francois, Constance Agamasu, De Chen, Jeevapani J Hettige, Timothy Travers, Sumantra Sarkar, Michael P Surh, Yue Yang, Adam Moody, Shusen Liu, Brian C Van Essen, Arthur F Voter, Arvind Ramanathan, Nicolas W Hengartner, Dhirendra K Simanshu, Andrew G Stephen, Peer-Timo Bremer, S Gnanakaran, James N Glosli, Felice C Lightstone, Frank McCormick, Dwight V Nissley, Frederick H Streitz.
      RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.
    Keywords:  RAS dynamics; RAS-membrane biology; massive parallel simulations; multiscale infrastructure; multiscale modeling
    DOI:  https://doi.org/10.1073/pnas.2113297119
  6. Biochem Biophys Rep. 2022 Mar;29 101191
    Biochemical characterization of the interaction between KRAS and Argonaute 2.
    Jessica J Waninger, Tyler S Beyett, Varun V Gadkari, Ronald F Siebenaler, Carson Kenum, Sunita Shankar, Brandon T Ruotolo, Arul M Chinnaiyan, John J G Tesmer.
      Oncogenic mutations in KRAS result in a constitutively active, GTP-bound form that in turn activates many proliferative pathways. However, because of its compact and simple architecture, directly targeting KRAS with small molecule drugs has been challenging. Another approach is to identify targetable proteins that interact with KRAS. Argonaute 2 (AGO2) was recently identified as a protein that facilitates RAS-driven oncogenesis. Whereas previous studies described the in vivo effect of AGO2 on cancer progression in cells harboring mutated KRAS, here we sought to examine their direct interaction using purified proteins. We show that full length AGO2 co-immunoprecipitates with KRAS using purified components, however, a complex between FL AGO2 and KRAS could not be isolated. We also generated a smaller N-terminal fragment of AGO2 (NtAGO2) which is believed to represent the primary binding site of KRAS. A complex with NtAGO2 could be detected via ion-mobility mass spectrometry and size exclusion chromatography. However, the data suggest that the interaction of KRAS with purified AGO2 (NtAGO2 or FL AGO2) is weak and likely requires additional cellular components or proteo-forms of AGO2 that are not readily available in our purified assay systems. Future studies are needed to determine what conformation or modifications of AGO2 are necessary to enrich KRAS association and regulate its activities.
    DOI:  https://doi.org/10.1016/j.bbrep.2021.101191
  7. FEBS Lett. 2022 Jan 06.
    PIP3 abundance overcomes PI3K signaling selectivity in invadopodia.
    Charles T Jakubik, Claire C Weckerly, Gerald R V Hammond, Anne R Bresnick, Jonathan M Backer.
      PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2 . We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short chain diC8-PIP3  rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2  is SHIP2-independent. Surprisingly, expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function, and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.
    Keywords:  PI 3-kinase; invadopodia; matrix degradation
    DOI:  https://doi.org/10.1002/1873-3468.14273
  8. J Clin Transl Res. 2021 Dec 28. 7(6): 771-785
    Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives.
    Rodrigo Motta, Santiago Cabezas-Camarero, Cesar Torres-Mattos, Alejandro Riquelme, Ana Calle, Paola Montenegro, Miguel J Sotelo.
       Background: Colorectal cancer is one of the most frequent neoplasms worldwide, and the majority of patients are diagnosed in advanced stages. Metastatic colorectal cancer (mCRC) harbors several mutations with different prognostic and predictive values; KRAS, NRAS, and BRAF mutations are the best known. Indeed, RAS and BRAF molecular status are associated with a different response to monoclonal antibodies (Anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor agents), which are usually added to chemotherapy in first-line, and thus allow to select the optimal therapy for patients with mCRC. Furthermore, sidedness is an important predictive and prognostic factor in mCRC, which is explained by the different molecular profile of left and right-sided tumors. Recently, microsatellite instability-high has emerged as a predictive factor of response and survival from immune checkpoint inhibitors in mCRC. Finally, several other alterations have been described in lower frequencies, such as human epidermal growth factor receptor-2 overexpression/amplification, PIK3CA pathway alterations, phosphatase and tension homolog loss, and hepatocyte growth factor/mesenchymal-epithelial transition factor pathway dysregulation, with several targeted therapies already demonstrating activity or being tested in currently ongoing clinical trials.
    Aim: To review the importance of studying the predictive and prognostic roles of the molecular profile of mCRC, the changes occurred in recent years and how they would potentially change in the near future, to guide physicians in treatment decisions.
    Relevance for Patients: Today, several different therapeutic options can be offered to patients in the first-line setting of mCRC. Therapies at present approved or under investigation in clinical trials will be thoroughly reviewed, with special emphasis on the molecular rationale behind them. Understanding the molecular status, resistance mechanisms and potential new druggable targets may allow physicians to choose the best therapeutic option in the first-line mCRC.
    Keywords:  first-line; metastatic colorectal cancer; mutation; personalized therapy; precision medicine
  9. Proc Natl Acad Sci U S A. 2022 Jan 11. pii: e2115261119. [Epub ahead of print]119(2):
    Photosynthetic assimilation of CO2 regulates TOR activity.
    Manuel J Mallén-Ponce, María Esther Pérez-Pérez, José L Crespo.
      The target of rapamycin (TOR) kinase is a master regulator that integrates nutrient signals to promote cell growth in all eukaryotes. It is well established that amino acids and glucose are major regulators of TOR signaling in yeast and metazoan, but whether and how TOR responds to carbon availability in photosynthetic organisms is less understood. In this study, we showed that photosynthetic assimilation of CO2 by the Calvin-Benson-Bassham (CBB) cycle regulates TOR activity in the model single-celled microalga Chlamydomonas reinhardtii Stimulation of CO2 fixation boosted TOR activity, whereas inhibition of the CBB cycle and photosynthesis down-regulated TOR. We uncovered a tight link between TOR activity and the endogenous level of a set of amino acids including Ala, Glu, Gln, Leu, and Val through the modulation of CO2 fixation and the use of amino acid synthesis inhibitors. Moreover, the finding that the Chlamydomonas starch-deficient mutant sta6 displayed disproportionate TOR activity and high levels of most amino acids, particularly Gln, further connected carbon assimilation and amino acids to TOR signaling. Thus, our results showed that CO2 fixation regulates TOR signaling, likely through the synthesis of key amino acids.
    Keywords:  CO2; Chlamydomonas; TOR kinase; amino acids
    DOI:  https://doi.org/10.1073/pnas.2115261119
  10. Clin Transl Oncol. 2022 Jan 07.
    Monitoring of RAS mutant clones in plasma of patients with RAS mutant metastatic colorectal cancer.
    A Fernández Montes, E Élez, A Vivancos, N Martínez, P González, M Covela, J de la Cámara, A Cousillas, J C Méndez, B Graña, E Aranda.
       PURPOSE: Some patients with histologically confirmed primary mCRC and mutated RAS reported undetectable RAS mutant clones in plasma after receiving anti-VEGF treatment. The aim was to prospectively assess it with its potential therapeutic implications.
    METHODS: RAS mutant genes in solid biopsy (before first-line treatment: FOLFOX/CAPOX + bevacizumab) were compared in liquid biopsy (before second-line treatment: panitumumab + FOLFIRI), using Idylla™ system. Discordant results between solid/liquid biopsies were assessed by the next-generation sequencing (NGS) test (solid/liquid biopsies).
    RESULTS: Twenty-three patients were assessed (seven had RAS mutant discrepancies between solid/liquid biopsies). The NGS test confirmed that 3/23 (13%) patients had undetectable RAS mutant clones in liquid biopsy and 3/23 (13%) presented discrepancies in solid biopsy (Idylla™ system vs. NGS test).
    CONCLUSION: Thirteen percentage of patients had undetectable RAS mutant clones in liquid biopsy after first-line treatment. However, some discrepancies between solid and liquid biopsies have been observed. These results suggest a need to improve accuracy of RAS analyses, especially in solid biopsies.
    Keywords:  Circulating tumor DNA; EGFR inhibitors; Liquid biopsy; Metastatic colorectal cancer; RAS mutant
    DOI:  https://doi.org/10.1007/s12094-021-02767-7
  11. Cell Stem Cell. 2022 Jan 06. pii: S1934-5909(21)00487-2. [Epub ahead of print]29(1): 3-4
    Enteric glia bring fresh WNT to the intestinal stem cell niche.
    Fränze Progatzky, Vassilis Pachnis.
      Intestinal stem cells continuously self-renew and differentiate into a variety of specialized epithelial cells that maintain gut health. New research in this issue of Cell Stem Cell (Baghdadi et al., 2022) shows that enteric glial cells regulate the intestinal stem cell niche during regeneration and disease through the production of WNT ligands.
    DOI:  https://doi.org/10.1016/j.stem.2021.12.003
  12. Comput Math Methods Med. 2021 ;2021 3953442
    Analysis of KRAS Mutation Status Prediction Model for Colorectal Cancer Based on Medical Imaging.
    Zhen Ren, Jin Che, Xiao Wei Wu, Jun Xia.
      This study retrospectively included some patients with colorectal cancer diagnosed by histopathology, to explore the feasibility of CT medical image texture analysis in predicting KRAS gene mutations in patients with colorectal cancer. Before any surgical procedure, all patients received an enhanced CT scan of the abdomen and pelvis, as well as genetic testing. To define patient groups, divide all patients into test and validation sets based on the order of patient enrollment. A radiologist took a look at the plain axial CT image of the tumor, as well as the portal vein CT image, at the corresponding level. The physician points the computer's cursor to the relevant area in the image, and TexRAD software programs together texture parameters based on various spatial scale factors, also known as total mean, total variance, statistical entropy, overall total average, mean total, positive mean, skewness value, kurtosis value, and general skewness. Using the same method again two weeks later, the observer and another physician measured the image of each patient again to see if the method was consistent between observers. With regard to clinical information, the KRAS gene mutation group and the wild group of participants in the test set and validation set each had values for the texture parameter. In a study of patients with colorectal cancer, the results demonstrated that CT texture parameters were correlated with the presence of the KRAS gene mutation. The best CT prediction model includes the values of the medium texture image's slope and the other CT fine texture image's value of entropy, the medium texture image's slope and kurtosis, and the medium texture image's mean and the other CT fine texture image's value of entropy. Regardless of the training set or the validation set, patients with and without KRAS gene mutations did not differ significantly in clinical characteristics. This method can be used to identify mutations in the KRAS gene in patients with colorectal cancer, making it practical to implement CT medical image texture analysis technology for that purpose.
    DOI:  https://doi.org/10.1155/2021/3953442
  13. Cell Mol Biol Lett. 2022 Jan 03. 27(1): 2
    The functions and roles of sestrins in regulating human diseases.
    Yitong Chen, Tingben Huang, Zhou Yu, Qiong Yu, Ying Wang, Ji'an Hu, Jiejun Shi, Guoli Yang.
      Sestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More significantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process.
    Keywords:  Biological functions; Biomarker; Human diseases; Musculoskeletal system disease; Sestrins; Therapeutic target
    DOI:  https://doi.org/10.1186/s11658-021-00302-8
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