bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2024–06–23
three papers selected by
Lucas B. Zeiger
  1. The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.
  2. Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.
  3. Genetic Insights into Colorectal Cancer: Evaluating PI3K/AKT Signaling Pathway Genes Expression.
  1. Mol Cancer Ther. 2024 Jun 21. OF1-OF13
    The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.
    Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Lars D Engstrom, Jade Laguer, Andrew Calinisan, Allan Hebbert, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, John M Ketcham, Anthony Ivetac, Christopher R Smith, J David Lawson, Lisa Rahbaek, Jeffrey Clarine, Natalie Nguyen, Barbara Saechao, Cody Parker, Adam J Elliott, Darin Vanderpool, Leo He, Laura D Hover, Julio Fernandez-Banet, Silvia Coma, Jonathan A Pachter, Jill Hallin, Matthew A Marx, David M Briere, James G Christensen, Peter Olson, Jacob Haling, Shilpi Khare.
      KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-23-0870
  2. Sci Adv. 2024 Jun 21. 10(25): eadi0707
    Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.
    Albert A Lee, Neil H Kim, Steven Alvarez, He Ren, Joseph B DeGrandchamp, L J Nugent Lew, Jay T Groves.
      Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of deterministic bistability but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts deterministic bistability and may be more resistant to pharmacological inhibition.
    DOI:  https://doi.org/10.1126/sciadv.adi0707
  3. Int J Mol Sci. 2024 May 27. pii: 5806. [Epub ahead of print]25(11):
    Genetic Insights into Colorectal Cancer: Evaluating PI3K/AKT Signaling Pathway Genes Expression.
    Rafał Świechowski, Jacek Pietrzak, Agnieszka Wosiak, Michał Mik, Ewa Balcerczak.
      The PI3K/AKT pathway plays a pivotal role in cellular processes, and its dysregulation is implicated in various cancers, including colorectal cancer. The present study correlates the expression levels of critical genes (PIK3CA, PTEN, AKT1, FOXO1, and FRAP) in 60 tumor tissues with clinicopathological and demographic characteristics. The results indicate age-related variation in FOXO1 gene expression, with higher levels observed in patients aged 68 and above. In addition, tumors originating from the rectum exhibit higher FOXO1 expression compared to colon tumors, suggesting region-specific differences in expression. The results also identify the potential correlation between PTEN, PIK3CA gene expression, and parameters such as tumor grade and neuroinvasion. The bioinformatic comparative analysis found that PTEN and FOXO1 expressions were downregulated in colorectal cancer tissue compared to normal colon tissue. Relapse-free survival analysis based on gene expression identified significant correlations, highlighting PTEN and FRAP as potential indicators of favorable outcomes. Our findings provide a deeper understanding of the role of the PI3K/AKT pathway in colorectal cancer and the importance of understanding the molecular basis of colorectal cancer development and progression.
    Keywords:  AKT1; PI3K/AKT pathway; PIK3CA; colorectal cancer; gene expression
    DOI:  https://doi.org/10.3390/ijms25115806
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