bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2024–02–11
nine papers selected by
Lucas B. Zeiger
  1. Precision Targeting of Mutant PI3Kα.
  2. A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.
  3. RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.
  4. Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance.
  5. Signaling from RAS to RAF: The Molecules and Their Mechanisms.
  6. Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer.
  7. Molecular pathological classification of colorectal cancer-an update.
  8. Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.
  9. The colorectal cancer drug market.
  1. Cancer Discov. 2024 Feb 08. 14(2): 204-207
    Precision Targeting of Mutant PI3Kα.
    Grace Q Gong, Bart Vanhaesebroeck.
      PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. In two back-to-back papers, Varkaris and colleagues report on the development of a novel allosteric PI3Kα-mutant-selective inhibitor and early clinical experience with this compound. See related article by Varkaris et al., p. 227 (6) . See related article by Varkaris et al., p. 240 (5) .
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1392
  2. bioRxiv. 2024 Jan 24. pii: 2023.05.17.541233. [Epub ahead of print]
    A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.
    Jeremy B Foote, Tyler E Mattox, Adam B Keeton, Xi Chen, Forrest T Smith, Kristy L Berry, Thomas Holmes, Junwei Wang, Chung-Hui Huang, Antonio B Ward, Cherlene Hardy, Karrianne G Fleten, Kjersti Flatmark, Karina J Yoon, Sujith Sarvesh, Puranchandra Nagaraju Ganji, Yulia Maxuitenko, Jacob Valiyaveettil, Julienne L Carstens, Donald J Buchsbaum, Jennifer Yang, Gang Zhou, Elmar Nurmemmedov, Ivan Babic, Vadim Gaponenko, Hazem Abdelkarim, Amit K Mitra, Michael R Boyd, Upender Manne, Sejong Bae, Bassel F El-Rayes, Gary A Piazza.
      Here we characterize a novel pan-RAS inhibitor, ADT-007, that potently and selectively inhibited the growth of histologically diverse cancer cell lines with mutant or activated RAS irrespective of the RAS mutation or isozyme. Growth inhibition was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-007 bound RAS in lysates from sensitive cells with sub-nanomolar EC 50 values but did not bind RAS in lysates from insensitive cells with low activated RAS. Insensitivity to ADT-007 was attributed to metabolic deactivation by UGT-mediated glucuronidation, providing a detoxification mechanism to protect normal cells from pan-RAS inhibition. Molecular modeling and experiments using recombinant RAS revealed that ADT-007 binds RAS in a nucleotide-free conformation to block GTP activation. Local injection of ADT-007 strongly inhibited tumor growth in syngeneic immune competent and xenogeneic immune deficient mouse models of colorectal and pancreatic cancer and activated innate and adaptive immunity in the tumor microenvironment.
    SIGNIFICANCE: ADT-007 is a novel pan-RAS inhibitor with a unique mechanism of action having potential to circumvent resistance to mutant-specific KRAS inhibitors and activate antitumor immunity. The findings support further development of ADT-007 analogs and/or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy for RAS mutant cancers.
    BACKGROUND: It is projected that colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDA) will cause 52,580 and 49,830 deaths in the US in 2023, respectively (1). The 5-year survival rates for CRC and PDA are 65% and 12%, respectively (1). Over 50% of CRC and 90% of PDA patients harbor mutations in KRAS genes that are associated with poor prognosis, making the development of novel KRAS inhibitors an urgent unmet medical need (2).
    DOI:  https://doi.org/10.1101/2023.05.17.541233
  3. J Cell Biol. 2024 May 06. pii: e202307121. [Epub ahead of print]223(5):
    RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.
    Neha Arora, Huanwen Mu, Hong Liang, Wenting Zhao, Yong Zhou.
      Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.
    DOI:  https://doi.org/10.1083/jcb.202307121
  4. Bioorg Med Chem. 2024 Feb 01. pii: S0968-0896(24)00041-5. [Epub ahead of print]100 117627
    Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance.
    Zhiyan Jiang, Yan Li, Xin Zhou, Jie Wen, Pengwu Zheng, Wufu Zhu.
      KRAS (Kirsten-RAS) is a highly mutated gene in the RAS (rat sarcoma) gene family that acts as a critical switch in intracellular signaling pathways, regulating cell proliferation, differentiation, and survival. The continuous activation of KRAS protein resulting from mutations leads to the activation of multiple downstream signaling pathways, inducing the development of malignant tumors. Despite the significant role of KRAS in tumorigenesis, targeted drugs against KRAS gene mutations have failed, and KRAS was once considered an undruggable target. The development of KRAS G12C mutant conformational modulators and the introduction of Sotorasib (R&D code: AMG510) have been a breakthrough in this field, with its remarkable clinical outcomes. Consequently, there is now a great number of KRAS G12C mutations. Patent applications for mutant GTPase KRAS G12C inhibitors, which are said to be covalently modified by cysteine codon 12, have been submitted since 2014. This review classifies KRAS G12C inhibitors based on their chemical structure and evaluates their biological properties. Additionally, it discusses the obstacles encountered in KRAS inhibitor research and the corresponding solutions.
    Keywords:  Anticancer agents; G12C; KRAS; Mutation; Research progress
    DOI:  https://doi.org/10.1016/j.bmc.2024.117627
  5. Annu Rev Biochem. 2024 Feb 05.
    Signaling from RAS to RAF: The Molecules and Their Mechanisms.
    Hyesung Jeon, Emre Tkacik, Michael J Eck.
      RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase complex, and RAF engagement with HSP90-CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway). Expected final online publication date for the Annual Review of Biochemistry , Volume 93 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-052521-040754
  6. J Transl Med. 2024 Feb 03. 22(1): 132
    Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer.
    Huan Yang, Xing Xiao, Leli Zeng, Haiteng Zeng, Yueyuan Zheng, Jingshu Wang, Guanghua Li, Weigang Dai, Yulong He, Suihai Wang, Jianjun Peng, Wei Chen.
       BACKGROUND: The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients.
    METHODS: Colorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models.
    RESULTS: A total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients.
    CONCLUSION: Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.
    Keywords:  Alpelisib; Colorectal cancer; Liquid biopsy; Organoid; PIK3CA; cfDNA
    DOI:  https://doi.org/10.1186/s12967-023-04675-6
  7. Virchows Arch. 2024 Feb 06.
    Molecular pathological classification of colorectal cancer-an update.
    Philip D Dunne, Mark J Arends.
      Colorectal cancer (CRC) has a broad range of molecular alterations with two major mechanisms of genomic instability (chromosomal instability and microsatellite instability) and has been subclassified into 4 consensus molecular subtypes (CMS) based on bulk RNA sequence data. Here, we update the molecular pathological classification of CRC with an overview of more recent bulk and single-cell RNA data analysis for development of transcriptional classifiers and risk stratification methods, taking into account the marked inter-tumoural and intra-tumoural heterogeneity of CRC. The importance of the stromal and immune components or tumour microenvironment (TME) to prognosis has emerged from these analyses. Attempts to remove the contribution of the tumour microenvironment and reveal neoplastic-specific transcriptional traits involved identification of the CRC intrinsic subtypes (CRIS). The use of immunohistochemistry and digital pathology to implement classification systems are evolving fields. Conventional adenoma versus serrated polyp pathway transcriptomic analysis and characterisation of canonical LGR5+ crypt base columnar stem cell versus ANXA1+ regenerative stem cell phenotypes emerged as key properties for improved understanding of transcriptional signals involved in molecular subclassification of colorectal cancers. Recently, classification by three pathway-derived subtypes (PDS1-3) has been developed, revealing a continuum of intrinsic biology associated with biological, stem cell, histopathological, and clinical attributes.
    Keywords:  Colorectal cancer; Hereditary; Molecular pathological classification
    DOI:  https://doi.org/10.1007/s00428-024-03746-3
  8. Sci Adv. 2024 Feb 09. 10(6): eadi2671
    Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.
    Jaakko Mattila, Arto Viitanen, Gaia Fabris, Tetiana Strutynska, Jerome Korzelius, Ville Hietakangas.
      The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation. We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.
    DOI:  https://doi.org/10.1126/sciadv.adi2671
  9. Nat Rev Drug Discov. 2024 Feb 09.
    The colorectal cancer drug market.
    Laura Ramos García, Rachel M Webster.
      
    DOI:  https://doi.org/10.1038/d41573-024-00026-2
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:26.