bims-pimaco 2024-08-25 papers

Issue of 2024–08–25
six papers selected by
Lucas B. Zeiger

Nat Genet. 2024 Aug 21.

Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.

Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W J Hall, Christopher Bryant, Roshan K Sood, Joanna C Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H Jones.

Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.

DOI: https://doi.org/10.1038/s41588-024-01891-8

J Cancer Immunol (Wilmington). 2024 ;6(2): 62-69

Combining EGFR and KRAS G12C Inhibitors for KRAS G12C Mutated Advanced Colorectal Cancer.

Hirotaka Miyashita, David S Hong.

KRAS is a commonly mutated gene in advanced colorectal cancer (CRC). Recently, inhibitors of KRAS G12C were developed and have shown promising efficacy for KRAS G12C mutated non-small cell lung cancer. However, KRAS G12C inhibitor monotherapy has not demonstrated excellent efficacy for KRAS G12C mutated advanced CRC due to multiple resistance mechanisms, especially receptor tyrosine kinase (RTK) signaling activation. To overcome this resistance mechanism, various combinations of epithelial growth factor receptor (EGFR) and KRAS G12C inhibitors, including panitumumab plus sotorasib, have been investigated in clinical trials. The combination of EGFR and KRAS G12C inhibitors for KRAS G12C mutated CRC demonstrated overall response rates ranging from 26% to 62.5% in seven clinical trials of phase I to III, whose data are available so far. The median progression-free survival in these trials ranged from 3.9 to 8.1 months. These efficacy data suggest that KRAS G12C inhibitor combination with EGFR inhibitors is more effective for KRAS G12C mutated advanced CRC than KRAS G12C inhibitor monotherapy. They also showed reasonable safety of the combination regimen. Based on these results, phase III clinical trials are being conducted to investigate EGFR and KRAS G12C inhibitor combinations as a first or second-line treatment for KRAS G12C mutated advanced CRC. Furthermore, other KRAS G12C inhibitors, KRAS G12D inhibitors, and pan-RAS inhibitors are being developed, which could make more patients with advanced CRC eligible for KRAS inhibition.

Keywords: Clinical trials; Colorectal cancer; KRAS; KRAS G12C inhibitors; RTK inhibitors

DOI: https://doi.org/10.33696/cancerimmunol.6.086

Semin Cancer Biol. 2024 Aug 14. pii: S1044-579X(24)00059-2. [Epub ahead of print]

Nutrient Sensing of mTORC1 signaling in cancer and aging.

Cong Jiang, Xiao Tan, Ning Liu, Peiqiang Yan, Tao Hou, Wenyi Wei.

The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.

Keywords: amino acid; kinase; mTOR; mTORC1; mTORC2; nutrient sensing; phosphorylation; tumorigenesis

DOI: https://doi.org/10.1016/j.semcancer.2024.08.001

Protein Expr Purif. 2024 Aug 20. pii: S1046-5928(24)00154-2. [Epub ahead of print] 106582

Improved Production of Class I Phosphatidylinositol 4,5-bisphosphate 3-kinase.

Simon Messing, Stephanie R T Widmeyer, John-Paul Denson, Jennifer Mehalko, Vanessa E Wall, Matthew Drew, Kelly Snead, Min Hong, Carissa Grose, Dominic Esposito, William Gillette.

Phosphatidylinositol 4,5-bisphosphate 3-kinases (PI3K) are a family of kinases whose activity affects pathways needed for basic cell functions. As a result, PI3K is one of the most mutated genes in all human cancers and serves as an ideal therapeutic target for cancer treatment. Expanding on work done by other groups we improved protein yield to produce stable and pure protein using a variety of modifications including improved solubility tag, novel expression modalities, and optimized purification protocol and buffer. By these means, we achieved a 40-fold increase in yield for p110α/p85α and a 3-fold increase in p110α. We also used these protocols to produce comparable constructs of the β and δ isoforms of PI3K. Increased yield enhanced the efficiency of our downstream high throughput drug discovery efforts on the PIK3 family of kinases.

Keywords: PI3K; PIK3CA; Phosphoinositide 3-kinase; p110α; p110β; p110δ protein production; p85α

DOI: https://doi.org/10.1016/j.pep.2024.106582

Bioinform Biol Insights. 2024 ;18 11779322241269386

Overcoming Resistance in Cancer Therapy: Computational Exploration of PIK3CA Mutations, Unveiling Novel Non-Toxic Inhibitors, and Molecular Insights Into Targeting PI3Kα.

Ilham Kandoussi, Ghyzlane El Haddoumi, Mariam Mansouri, Lahcen Belyamani, Azeddine Ibrahimi, Rachid Eljaoudi.

Phosphoinositide-3-kinases (PI3 K) are pivotal regulators of cell signaling implicated in various cancers. Particularly, mutations in the PIK3CA gene encoding the p110α catalytic subunit drive oncogenic signaling, making it an attractive therapeutic target. Our study conducted in silico exploration of 31 PIK3CA mutations across breast, endometrial, colon, and ovarian cancers, assessing their impacts on response to PI3Kα inhibitors and identifying potential non-toxic inhibitors and also elucidating their effects on protein stability and flexibility. Specifically, we observed significant alterations in the stability and flexibility of the PI3 K protein induced by these mutations. Through molecular docking analysis, we evaluated the binding interactions between the selected inhibitors and the PI3 K protein. The filtration of ligands involved calculating chemical descriptors, incorporating Veber and Lipinski rules, as well as IC50 values and toxicity predictions. This process reduced the initial dataset of 1394 ligands to 12 potential non-toxic inhibitors, and four reference inhibitors with significant biological activity in clinical trials were then chosen based on their physico-chemical properties. This analysis revealed Lig5's exceptional performance, exhibiting superior affinity and specificity compared to established reference inhibitors such as pictilisib. Lig5 formed robust binding interactions with the PI3 K protein, suggesting its potential as a highly effective therapeutic agent against PI3 K-driven cancers. Furthermore, molecular dynamics simulations provided valuable insights into Lig5's stability and its interactions with PI3 K over 100 ns. These simulations supported Lig5's potential as a versatile inhibitor capable of effectively targeting various mutational profiles of PI3 K, thereby mitigating issues related to resistance and toxicity commonly associated with current inhibitors.

Keywords: PIK3CA mutations; Phosphoinositide-3-kinases; cancer; inhibitor screening; molecular docking; molecular dynamics simulation; personalized medicine

DOI: https://doi.org/10.1177/11779322241269386

Elife. 2024 Aug 20. pii: RP91012. [Epub ahead of print]12

Genetic code expansion, click chemistry, and light-activated PI3K reveal details of membrane protein trafficking downstream of receptor tyrosine kinases.

Duk-Su Koh, Anastasiia Stratiievska, Subhashis Jana, Shauna C Otto, Teresa M Swanson, Anthony Nhim, Sara Carlson, Marium Raza, Ligia Araujo Naves, Eric N Senning, Ryan A Mehl, Sharona E Gordon.

Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane.

Keywords: biochemistry; chemical biology; click chemistry; human; membrane protein; molecular biophysics; rat; structural biology; trafficking

DOI: https://doi.org/10.7554/eLife.91012