bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2024–05–12
seven papers selected by
Lucas B. Zeiger
  1. Molecular dissection of PI3Kβ synergistic activation by receptor tyrosine kinases, GβGγ, and Rho-family GTPases.
  2. State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies.
  3. Colorectal Cancer Stem Cell Subtypes Orchestrate Distinct Tumor Microenvironments.
  4. Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor.
  5. Protein expression of the amino acid transporter SLC7A5 in tumor tissue is prognostic in early-stage colorectal cancer.
  6. Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.
  7. 30 years of PI3K: an interview with Bart Vanhaesebroeck.
  1. Elife. 2024 May 07. pii: RP88991. [Epub ahead of print]12
    Molecular dissection of PI3Kβ synergistic activation by receptor tyrosine kinases, GβGγ, and Rho-family GTPases.
    Benjamin R Duewell, Naomi E Wilson, Gabriela M Bailey, Sarah E Peabody, Scott D Hansen.
      Phosphoinositide 3-kinase (PI3K) beta (PI3Kβ) is functionally unique in the ability to integrate signals derived from receptor tyrosine kinases (RTKs), G-protein coupled receptors, and Rho-family GTPases. The mechanism by which PI3Kβ prioritizes interactions with various membrane-tethered signaling inputs, however, remains unclear. Previous experiments did not determine whether interactions with membrane-tethered proteins primarily control PI3Kβ localization versus directly modulate lipid kinase activity. To address this gap in our knowledge, we established an assay to directly visualize how three distinct protein interactions regulate PI3Kβ when presented to the kinase in a biologically relevant configuration on supported lipid bilayers. Using single molecule Total Internal Reflection Fluorescence (TIRF) Microscopy, we determined the mechanism controlling PI3Kβ membrane localization, prioritization of signaling inputs, and lipid kinase activation. We find that auto-inhibited PI3Kβ prioritizes interactions with RTK-derived tyrosine phosphorylated (pY) peptides before engaging either GβGγ or Rac1(GTP). Although pY peptides strongly localize PI3Kβ to membranes, stimulation of lipid kinase activity is modest. In the presence of either pY/GβGγ or pY/Rac1(GTP), PI3Kβ activity is dramatically enhanced beyond what can be explained by simply increasing membrane localization. Instead, PI3Kβ is synergistically activated by pY/GβGγ and pY/Rac1 (GTP) through a mechanism consistent with allosteric regulation.
    Keywords:  G-proteins; GPCRs; Rho GTPases; biochemistry; chemical biology; human; phosphatidylinositol phosphate lipids; phosphoinositide 3-kinase; receptor tyrosine kinases
    DOI:  https://doi.org/10.7554/eLife.88991
  2. Curr Opin Oncol. 2024 Apr 22.
    State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies.
    Pieterjan Vanclooster, Sofie Seghers, Hans Prenen.
       PURPOSE OF REVIEW: Overall, the review underscores the evolving landscape of KRAS-targeted therapy and the potential for these approaches to improve outcomes for patients with gastrointestinal malignancies. It highlights the importance of ongoing research and clinical trials in advancing precision medicine strategies for KRAS-driven cancers. This review provides a comprehensive overview of the RAS signaling pathway and its significance in gastrointestinal malignancies.
    RECENT FINDINGS: The introduction of KRAS inhibitor represents a significant advancement in the treatment landscape for KRAS-mutant cancers. In this review, we discuss upcoming trends in KRAS-targeted therapy, including the development of mutant-specific direct KRAS inhibitors like MRTX1133 and pan-RAS inhibitors such as RMC-6236. It also explores indirect RAS inhibitors targeting upstream and downstream components of the RAS pathway. Additionally, the review examines other upcoming strategies like combination therapies, such as CDK4/6 and ERK MAPK inhibitors, as well as adoptive cell therapy and cancer vaccines targeting KRAS-mutant cancers.
    SUMMARY: Targeting RAS has become an important strategy in treating gastrointestinal cancer. These findings in this review underscore the importance of a multidisciplinary approach, integrating advances in molecular profiling, targeted therapy, immunotherapy, and clinical research to optimize treatment strategies for patients with KRAS-mutant gastrointestinal malignancies.
    DOI:  https://doi.org/10.1097/CCO.0000000000001042
  3. bioRxiv. 2024 Apr 27. pii: 2024.04.25.591144. [Epub ahead of print]
    Colorectal Cancer Stem Cell Subtypes Orchestrate Distinct Tumor Microenvironments.
    Linzi Hosohama, Delia F Tifrea, Kevin Nee, Sung Yun Park, Jie Wu, Amber N Habowski, Cassandra Van, Marcus M Seldin, Robert A Edwards, Marian L Waterman.
      Several classification systems have been developed to define tumor subtypes in colorectal cancer (CRC). One system proposes that tumor heterogeneity derives in part from distinct cancer stem cell populations that co-exist as admixtures of varying proportions. However, the lack of single cell resolution has prohibited a definitive identification of these types of stem cells and therefore any understanding of how each influence tumor phenotypes. Here were report the isolation and characterization of two cancer stem cell subtypes from the SW480 CRC cell line. We find these cancer stem cells are oncogenic versions of the normal Crypt Base Columnar (CBC) and Regenerative Stem Cell (RSC) populations from intestinal crypts and that their gene signatures are consistent with the "Admixture" and other CRC classification systems. Using publicly available single cell RNA sequencing (scRNAseq) data from CRC patients, we determine that RSC and CBC cancer stem cells are commonly co-present in human CRC. To characterize influences on the tumor microenvironment, we develop subtype-specific xenograft models and we define their tumor microenvironments at high resolution via scRNAseq. RSCs create differentiated, inflammatory, slow growing tumors. CBCs create proliferative, undifferentiated, invasive tumors. With this enhanced resolution, we unify current CRC patient classification schema with TME phenotypes and organization.
    DOI:  https://doi.org/10.1101/2024.04.25.591144
  4. Bioorg Med Chem Lett. 2024 May 05. pii: S0960-894X(24)00182-3. [Epub ahead of print]107 129780
    Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor.
    Kun Wang, Zehui Zhou, Xinyi Ma, Jiahang Xu, Wangyang Xu, Guizhen Zhou, Chuan Zhou, Huajie Li, Mingyue Zheng, Sulin Zhang, Tianfeng Xu.
      Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o-induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.
    Keywords:  Anti-cancer activity; KRAS mutation; PROTAC; SOS1
    DOI:  https://doi.org/10.1016/j.bmcl.2024.129780
  5. PLoS One. 2024 ;19(5): e0298362
    Protein expression of the amino acid transporter SLC7A5 in tumor tissue is prognostic in early-stage colorectal cancer.
    Makiko Ogawa, Atsushi Tanaka, Masaki Maekawa, Kei Namba, Yusuke Otani, Jinru Shia, Julia Y Wang, Michael H Roehrl.
      Proteins overexpressed in early-stage cancers may serve as early diagnosis and prognosis markers as well as targets for cancer therapies. In this study, we examined the expression of an essential amino acid carrier SLC7A5 (LAT1, CD98, or 4F2 light chain) in cancer tissue from two well-annotated cohorts of 575 cases of early-stage and 106 cases of late-stage colorectal cancer patients. Immunohistochemistry showed SLC7A5 overexpression in 72.0% of early-stage and 56.6% of late-stage cases. SLC7A5 expression was not influenced by patient gender, age, location, or mismatch repair status, although it appeared to be slightly less prevalent in tumors of mucinous differentiation or with lymphovascular invasion. Statistical analyses revealed a positive correlation between SLC7A5 overexpression and both overall survival and disease-free survival in early-stage but not late-stage cancers. Co-expression analyses of the TCGA and CPTAC colorectal cancer cohorts identified a network of gene transcripts positively related to SLC7A5, with its heterodimer partner SLC3A2 having the highest co-expression score. Network analysis uncovered the SLC7A network to be significantly associated with ncRNA such as tRNA processing and the mitotic cell cycle. Since SLC7A5 is also a marker of activated lymphocytes such as NK, T, and B lymphocytes, SLC7A5 overexpression in early colorectal cancers might trigger a strong anti-tumor immune response which could results in better clinical outcome. Overall, our study provides clear evidence of differential SLC7A5 expression and its prognostic value for early-stage colorectal cancer, although the understanding of its functions in colorectal tumorigenesis and cancer immunity is currently rather limited and awaits further characterization.
    DOI:  https://doi.org/10.1371/journal.pone.0298362
  6. Mol Metab. 2024 May 03. pii: S2212-8778(24)00083-8. [Epub ahead of print] 101952
    Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.
    Kiavash Hushmandi, Behzad Einollahi, Seyed Hassan Saadat, E Hui Clarissa Lee, Marzieh Ramezani Farani, Elena Okina, Yun Suk Huh, Noushin Nabavi, Shokooh Salimimoghadam, Alan Prem Kumar.
      Solute carrier (SLC), a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment. Amino acids are fundamental building blocks of cells, playing essential roles not only in protein synthesis but also in nutrient sensing, and in signaling pathways that can promote tumorigenesis. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. Amino acid uptake by SLCs positively affects tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although a body of studies evaluated the function of SLC7A11 and SLC1A5, some of the SLC proteins are not studied sufficiently in cancer. In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids, as one of the most important materials that cancer cells need, and their transporters within the SLC superfamily.
    Keywords:  Amino acid; Cancer; Cancer metabolism; Nutrient sensing; SLC
    DOI:  https://doi.org/10.1016/j.molmet.2024.101952
  7. Future Oncol. 2024 May 07.
    30 years of PI3K: an interview with Bart Vanhaesebroeck.
    Bart Vanhaesebroeck.
      
    Keywords:  PI3Kalpha; PI3Kdelta; cell signaling
    DOI:  https://doi.org/10.2217/fon-2024-0215
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