bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2021–09–26
twelve papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research
  1. KARATE: PKA-induced KRAS4B-RHOA-mTORC2 supercomplex phosphorylates AKT in insulin signaling and glucose homeostasis.
  2. Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.
  3. Phosphoproteomics identifies PI3K inhibitor-selective adaptive responses in pancreatic cancer cell therapy and resistance.
  4. Amino acids and mechanistic target of rapamycin regulate the fate of live engulfed cells.
  5. KRAS G12C fragment screening renders new binding pockets.
  6. CRMP5 regulates cell proliferation and development of colorectal cancer via MAPK-dependent signaling.
  7. AMPK: restoring metabolic homeostasis over space and time.
  8. KRAS and BRAF Mutations in Stage II/III Colon Cancer: A Systematic Review and Meta-Analysis.
  9. Supply and demand: Cellular nutrient uptake and exchange in cancer.
  10. Development of PI3K inhibitors: advances in clinical trials and new strategies (Review).
  11. Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells.
  12. Dissecting the biology of mTORC1 beyond rapamycin.
  1. Mol Cell. 2021 Sep 14. pii: S1097-2765(21)00735-8. [Epub ahead of print]
    KARATE: PKA-induced KRAS4B-RHOA-mTORC2 supercomplex phosphorylates AKT in insulin signaling and glucose homeostasis.
    Hiroshi Senoo, Daisuke Murata, May Wai, Kenta Arai, Wakiko Iwata, Hiromi Sesaki, Miho Iijima.
      AKT is a serine/threonine kinase that plays an important role in metabolism, cell growth, and cytoskeletal dynamics. AKT is activated by two kinases, PDK1 and mTORC2. Although the regulation of PDK1 is well understood, the mechanism that controls mTORC2 is unknown. Here, by investigating insulin receptor signaling in human cells and biochemical reconstitution, we found that insulin induces the activation of mTORC2 toward AKT by assembling a supercomplex with KRAS4B and RHOA GTPases, termed KARATE (KRAS4B-RHOA-mTORC2 Ensemble). Insulin-induced KARATE assembly is controlled via phosphorylation of GTP-bound KRAS4B at S181 and GDP-bound RHOA at S188 by protein kinase A. By developing a KARATE inhibitor, we demonstrate that KRAS4B-RHOA interaction drives KARATE formation. In adipocytes, KARATE controls insulin-dependent translocation of the glucose transporter GLUT4 to the plasma membrane for glucose uptake. Thus, our work reveals a fundamental mechanism that activates mTORC2 toward AKT in insulin-regulated glucose homeostasis.
    Keywords:  AKT; KRAS GTPase; PKA; RHOA GTPase; insulin; mTORC2
    DOI:  https://doi.org/10.1016/j.molcel.2021.09.001
  2. Cancer Lett. 2021 Sep 20. pii: S0304-3835(21)00471-7. [Epub ahead of print]522 129-141
    Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.
    Keita Hanada, Kenji Kawada, Gen Nishikawa, Kosuke Toda, Hisatsugu Maekawa, Yasuyo Nishikawa, Hideyuki Masui, Wataru Hirata, Michio Okamoto, Yoshiyuki Kiyasu, Shusaku Honma, Ryotaro Ogawa, Rei Mizuno, Yoshiro Itatani, Hiroyuki Miyoshi, Takehiko Sasazuki, Senji Shirasawa, M Mark Taketo, Kazutaka Obama, Yoshiharu Sakai.
      Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes. Recent studies have revealed macropinocytosis's important role in metabolic adaptation to nutrient stress in cancer cells harboring KRAS mutations. Here we showed that KRAS-mutant CRC cells enhanced macropinocytosis for tumor growth under nutrient-depleted conditions. We also demonstrated that activation of Rac1 and phosphoinositide 3-kinase were involved in macropinocytosis of KRAS-mutant CRC cells. Furthermore, we found that macropinocytosis was closely correlated with asparagine metabolism. In KRAS-mutant CRC cells engineered with knockdown of asparagine synthetase, macropinocytosis was accelerated under glutamine-depleted condition, and albumin addition could restore the glutamine depletion-induced growth suppression by recovering the intracellular asparagine level. Finally, we discovered that the combination of macropinocytosis inhibition and asparagine depletion dramatically suppressed the tumor growth of KRAS-mutant CRC cells in vivo. These results indicate that dual blockade of macropinocytosis and asparagine bioavailability could be a novel therapeutic strategy for KRAS-mutant cancers.
    Keywords:  Asparagine synthetase; KRAS mutation; Macropinocytosis; l-asparaginase
    DOI:  https://doi.org/10.1016/j.canlet.2021.09.023
  3. Mol Cancer Ther. 2021 Sep 22. pii: molcanther.0981.2020. [Epub ahead of print]
    Phosphoproteomics identifies PI3K inhibitor-selective adaptive responses in pancreatic cancer cell therapy and resistance.
    Celia Cintas, Thibault Douche, Zahra Dantes, Emmanuelle Mouton-Barbosa, Marie-Pierre Bousquet, Coralie Cayron, Nicole Therville, Frédéric Pont, Fernanda Ramos-Delgado, Camille Guyon, Barbara H Garmy-Susini, Paola Cappello, Odile Burlet-Schiltz, Emilio Hirsch, Anne Gomez-Brouchet, Benoît Thibault, Maximilian Reichert, Julie Guillermet-Guibert.
      The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform-selectivity towards PI3Kα, PI3Kβ or PI3Kγ (namely A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced re-activation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved a-selective BYL-719 with γ-selective IPI-549 was more efficient than single molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0981
  4. FASEB J. 2021 Oct;35(10): e21909
    Amino acids and mechanistic target of rapamycin regulate the fate of live engulfed cells.
    Sung Eun Kim, Justin Zhang, Enoch Jiang, Michael Overholtzer.
      Metabolic stress contributes to the regulation of cell death in normal and diseased tissues. While different forms of cell death are known to be regulated by metabolic stress, how the cell engulfment and killing mechanism entosis is regulated is not well understood. Here we find that the death of entotic cells is regulated by the presence of amino acids and activity of the mechanistic target of rapamycin (mTOR). Amino acid withdrawal or mTOR inhibition induces apoptosis of engulfed cells and blocks entotic cell death that is associated with the lipidation of the autophagy protein microtubule-associated protein light chain 3 (LC3) to entotic vacuoles. Two other live cell engulfment programs, homotypic cell cannibalism (HoCC) and anti-CD47 antibody-mediated phagocytosis, known as phagoptosis, also undergo a similar vacuole maturation sequence involving LC3 lipidation and lysosome fusion, but only HoCC involves mTOR-dependent regulation of vacuole maturation and engulfed cell death similar to entosis. We further find that the regulation of cell death by mTOR is independent of autophagy activation and instead involves the 4E-BP1/2 proteins that are known regulators of mRNA translation. Depletion of 4E-BP1/2 proteins can restore the mTOR-regulated changes of entotic death and apoptosis rates of engulfed cells. These results identify amino acid signaling and the mTOR-4E-BP1/2 pathway as an upstream regulation mechanism for the fate of live engulfed cells formed by entosis and HoCC.
    Keywords:  amino acids; cell death; entosis; mTOR; metabolism
    DOI:  https://doi.org/10.1096/fj.202100870R
  5. Small GTPases. 2021 Sep 24. 1-14
    KRAS G12C fragment screening renders new binding pockets.
    Magali Mathieu, Valérie Steier, Florence Fassy, Cécile Delorme, David Papin, Bruno Genet, Francis Duffieux, Thomas Bertrand, Laure Delarbre, Hélène Le-Borgne, Annick Parent, Patrick Didier, Jean-Pierre Marquette, Maryse Lowinski, Jacques Houtmann, Annabelle Lamberton, Laurent Debussche, Rak Alexey.
      KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.
    Keywords:  KRAS; covalent inhibitor; fragment screening; induced binding pocket
    DOI:  https://doi.org/10.1080/21541248.2021.1979360
  6. Oncol Lett. 2021 Nov;22(5): 747
    CRMP5 regulates cell proliferation and development of colorectal cancer via MAPK-dependent signaling.
    Fanghua Qiu, Lin Yu, Daoli Liu, Yujin Wu, Feng Qiu.
      Colorectal cancer (CRC) is one of the most common malignancies worldwide. Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that serve a major role in neural development. CRMP5 has been identified as a biomarker of numerous cancer types, including lung cancer and glioblastoma. However, the role of CRMP5 in CRC remains unclear. In the present study, CRMP5 was characterized as a novel biomarker of poor survival in CRC. CRMP5-overexpression in CRC cells promoted cell proliferation and migration while CPMP5-knockdown decreased cell growth and migration. A novel mechanism was uncovered, by which CRMP5 regulates MAPK signaling to drive CRC cell proliferation and development. Furthermore, CRMP5-overexpression induced chemotherapy resistance and tumor recurrence in CRC. Taken together, these results demonstrated the important role of CRMP5 in the development and proliferation of CRC cells and suggested that CRMP5 may be a novel therapeutic target for CRC.
    Keywords:  CRMP5; ERK1/2; MAPK signaling; colorectal cancer; migration; proliferation
    DOI:  https://doi.org/10.3892/ol.2021.13008
  7. Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00682-1. [Epub ahead of print]81(18): 3677-3690
    AMPK: restoring metabolic homeostasis over space and time.
    Elijah Trefts, Reuben J Shaw.
      The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.molcel.2021.08.015
  8. J Natl Cancer Inst. 2021 Sep 20. pii: djab190. [Epub ahead of print]
    KRAS and BRAF Mutations in Stage II/III Colon Cancer: A Systematic Review and Meta-Analysis.
    Vincenzo Formica, Francesco Sera, Chiara Cremolini, Silvia Riondino, Cristina Morelli, Hendrik-Tobias Arkenau, Mario Roselli.
       BACKGROUND: KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer, however their impact in the adjuvant setting has not yet been established.
    METHODS: We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS/BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS/OS (so-called 'multivariate') meta-analysis was performed. All statistical tests were 2-sided.
    RESULTS: Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled HR = 1.36, 95% CI = 1.15-1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03-1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00-1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31-1.70, P < .001). MSI adjustment enhanced the effect of the mutations on outcome in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15-1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03-1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22-2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37-2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (P interaction = 0.02). This interaction was even more pronounced in the DFS/OS multivariate meta-analysis.
    CONCLUSIONS: Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.
    DOI:  https://doi.org/10.1093/jnci/djab190
  9. Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00693-6. [Epub ahead of print]81(18): 3731-3748
    Supply and demand: Cellular nutrient uptake and exchange in cancer.
    Vasileios Papalazarou, Oliver D K Maddocks.
      Nutrient supply and demand delineate cell behavior in health and disease. Mammalian cells have developed multiple strategies to secure the necessary nutrients that fuel their metabolic needs. This is more evident upon disruption of homeostasis in conditions such as cancer, when cells display high proliferation rates in energetically challenging conditions where nutritional sources may be scarce. Here, we summarize the main routes of nutrient acquisition that fuel mammalian cells and their implications in tumorigenesis. We argue that the molecular mechanisms of nutrient acquisition not only tip the balance between nutrient supply and demand but also determine cell behavior upon nutrient limitation and energetic stress and contribute to nutrient partitioning and metabolic coordination between different cell types in inflamed or tumorigenic environments.
    Keywords:  SLC proteins; amino acid; cancer; nutrient scavenging; nutrient transport; nutrient transporters
    DOI:  https://doi.org/10.1016/j.molcel.2021.08.026
  10. Pharmacol Res. 2021 Sep 18. pii: S1043-6618(21)00484-9. [Epub ahead of print] 105900
    Development of PI3K inhibitors: advances in clinical trials and new strategies (Review).
    Dandan Meng, Wei He, Yan Zhang, Zhenguo Liang, Jinling Zheng, Xu Zhang, Xing Zheng, Peng Zhan, Hongfei Chen, Wenjun Li, Lintao Cai.
      Phosphatidylinositol 3-kinases (PI3Ks) are the family of vital lipid kinases widely distributed in mammalian cells. The overexpression of PI3Ks leads to hyperactivation of the PI3K/AKT/mTOR pathway, which is considered a pivotal pathway in the occurrence and development of tumors. Hence, PI3Ks are viewed as promising therapeutic targets for anti-cancer therapy. To date, some PI3K inhibitors have achieved desired therapeutic effect via inhibiting the activity of PI3Ks or reducing the level of PI3Ks in clinical trials, among which, Idelalisib, Alpelisib and Duvelisib have been approved by the FDA for treatment of ER+/HER2- advanced metastatic breast cancer and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphomas (SLL). This review focuses on the latest advances of PI3K inhibitors with efficacious anticancer activity, which are classified into Pan-PI3K inhibitors, isoform-specific PI3K inhibitors and dual PI3K/mTOR inhibitors based on the isoform affinity. Their corresponding structure characteristics and structures-activity relationship (SAR), together with the progress in the clinical application are mainly discussed. Additionally, the new PI3K inhibitory strategy, such as PI3K degradation agent, for the design of potential PI3K candidates to overcome drug resistance is referred as well.
    Keywords:  PI3K/AKT/mTOR pathway; PI3Ks; cancers; inhibitors
    DOI:  https://doi.org/10.1016/j.phrs.2021.105900
  11. Front Oncol. 2021 ;11 641453
    Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells.
    Rui-Zhen Cao, Li Min, Si Liu, Ru-Yue Tian, Hai-Yan Jiang, Juan Liu, Lin-Lin Shao, Rui Cheng, Sheng-Tao Zhu, Shui-Long Guo, Peng Li.
       Background: Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) protein is a core subunit of mammalian target of rapamycin complex 2, and is associated with cancer progression. However, the biological function of Rictor in cancer, particularly its clinical relevance in gastric cancer (GC) remains largely unknown.
    Methods: Rictor expression and its association with clinicopathologic characteristics in GC were analyzed by immunohistochemistry. Effect of Rictor and Caveolin-1 (Cav 1) on GC cells apoptosis was evaluated via overexpression experiment in vitro. Mechanisms of Rictor and Cav 1 in GC were explored through overexpression and knockdown, by immunofluorescence and western blot analyses.
    Results: Rictor was upregulated in GC, and mainly located in the cytoplasm of cancer cells. Moreover, higher Rictor levels were associated with worse prognosis. Rictor could inhibit GC cell apoptosis and promote cell growth in vitro. The results of immunofluorescence revealed that Cav 1 localized in GC cell membrane but did not co-localize with Rictor. Further, Rictor regulated apoptosis-related proteins, long non-coding RNAs and also activated cellular signaling, thereby positively regulating Cav 1 expression. This effect was attenuated by the Akt inhibitor ly294002. Cav 1 did not significantly affect the ability of Rictor to inhibit tumor cell apoptosis.
    Conclusions: Rictor is upregulated in GC and associated with worse prognosis. It inhibits tumor apoptosis and activates Cav 1 through the Akt signaling pathway to inhibit the apoptosis of GC cells. Rictor is, therefore, a promising prognostic biomarker and possible therapeutic target in GC patients.
    Keywords:  Akt; Apoptosis; Cav 1; Gastric cancer; Rictor
    DOI:  https://doi.org/10.3389/fonc.2021.641453
  12. Sci Signal. 2021 Sep 21. 14(701): eabe0161
    Dissecting the biology of mTORC1 beyond rapamycin.
    Guang Yang, Deanne Francis, James R Krycer, Mark Larance, Ziyang Zhang, Chris J Novotny, Alexis Diaz-Vegas, Kevan M Shokat, David E James.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/scisignal.abe0161
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