bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2023‒01‒15
eighteen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
  1. Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.
  2. GATOR2 rings GATOR1 to speak to mTORC1.
  3. α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.
  4. Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.
  5. KRAS inhibitors gather momentum.
  6. KRAS inhibition in metastatic colorectal cancer: An update.
  7. The Prevalence of BRAF, PIK3CA, and RAS Mutations in Indian Patients with Colorectal Cancer.
  8. Alpelisib Efficacy Without Cherry-PI3King Mutations.
  9. Targeting KRAS G12C mutations in colorectal cancer.
  10. Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer.
  11. The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region.
  12. PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia.
  13. An atlas of substrate specificities for the human serine/threonine kinome.
  14. Discovery of a novel ATP-competitive MEK inhibitor DS03090629 that overcomes resistance conferred by BRAF overexpression in BRAF-mutated melanoma.
  15. Transcriptional activity mediated by β-CATENIN and TCF/LEF family members is completely dispensable for survival and propagation of multiple human colorectal cancer cell lines.
  16. Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
  17. Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors.
  18. SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.
  1. Nat Commun. 2023 Jan 12. 14(1): 181
    Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.
    Meredith L Jenkins, Harish Ranga-Prasad, Matthew A H Parson, Noah J Harris, Manoj K Rathinaswamy, John E Burke.
      PIK3CA encoding the phosphoinositide 3-kinase (PI3K) p110α catalytic subunit is frequently mutated in cancer, with mutations occurring widely throughout the primary sequence. The full set of mechanisms underlying how PI3Ks are activated by all oncogenic mutations on membranes are unclear. Using a synergy of biochemical assays and hydrogen deuterium exchange mass spectrometry (HDX-MS), we reveal unique regulatory mechanisms underlying PI3K activation. Engagement of p110α on membranes leads to disengagement of the ABD of p110α from the catalytic core, and the C2 domain from the iSH2 domain of the p85 regulatory subunit. PI3K activation also requires reorientation of the p110α C-terminus, with mutations that alter the inhibited conformation of the C-terminus increasing membrane binding. Mutations at the C-terminus (M1043I/L, H1047R, G1049R, and N1068KLKR) activate p110α through distinct mechanisms, with this having important implications for mutant selective inhibitor development. This work reveals unique mechanisms underlying how PI3K is activated by oncogenic mutations, and explains how double mutants can synergistically increase PI3K activity.
    DOI:  https://doi.org/10.1038/s41467-023-35789-6
  2. Mol Cell. 2023 Jan 05. pii: S1097-2765(22)01168-6. [Epub ahead of print]83(1): 6-8
    GATOR2 rings GATOR1 to speak to mTORC1.
    Umakant Sahu, Issam Ben-Sahra.
      The mechanistic target of rapamycin complex 1 (mTORC1) senses cellular leucine levels through the GATOR1/2-Rag axis. Jiang et al. show that the Ring domains of GATOR2 subunits maintain the integrity of the complex and promote ubiquitination and inhibition of GATOR1, thereby leading to mTORC1 activation.
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.011
  3. Int J Mol Sci. 2023 Jan 01. pii: 748. [Epub ahead of print]24(1):
    α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.
    Baraa Abuasaker, Eduardo Garrido, Marta Vilaplana, Jesús Daniel Gómez-Zepeda, Sonia Brun, Marta Garcia-Cajide, Caroline Mauvezin, Montserrat Jaumot, Maria Dolors Pujol, Jaime Rubio-Martínez, Neus Agell.
      KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the α4-α5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling.
    Keywords:  AKT; ERK; KRAS; RAF; allosteric pocket; calmodulin; colorectal cancer; docking; molecular dynamics; small molecule inhibitors
    DOI:  https://doi.org/10.3390/ijms24010748
  4. Nat Cell Biol. 2023 Jan 12.
    Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.
    Rui Tang, Emily G Shuldiner, Marcus Kelly, Christopher W Murray, Jess D Hebert, Laura Andrejka, Min K Tsai, Nicholas W Hughes, Mitchell I Parker, Hongchen Cai, Yao-Cheng Li, Geoffrey M Wahl, Roland L Dunbrack, Peter K Jackson, Dmitri A Petrov, Monte M Winslow.
      Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRASG12D-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.
    DOI:  https://doi.org/10.1038/s41556-022-01049-w
  5. Nat Med. 2023 Jan 10.
    KRAS inhibitors gather momentum.
    Karen O'Leary.
      
    Keywords:  Cancer therapy; Clinical trials; Targeted therapies
    DOI:  https://doi.org/10.1038/d41591-023-00006-w
  6. Curr Opin Pharmacol. 2023 Jan 11. pii: S1471-4892(22)00170-9. [Epub ahead of print]68 102343
    KRAS inhibition in metastatic colorectal cancer: An update.
    Maliha Nusrat, Rona Yaeger.
      About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRASG12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.
    DOI:  https://doi.org/10.1016/j.coph.2022.102343
  7. South Asian J Cancer. 2022 Jul;11(3): 190-194
    The Prevalence of BRAF, PIK3CA, and RAS Mutations in Indian Patients with Colorectal Cancer.
    Omshree Shetty, Vaibhavi Vengurlekar, Akhil Kapoor, Vishakha Kamble, Mamta Gurav, Prabhat Bhargava, Sujay Srinivas, Anant Ramaswamy, Mukta Ramadwar, Avanish P Saklani, Ashwin Desouza, Vikas Ostwal.
      Omshree ShettyVikas OstwalIntroduction  The present study evaluates the mutation pattern and frequency of BRAF , PIK3CA and RAS in colorectal carcinoma observed in the tertiary cancer center in India. Materials and Methods  Consecutive cases of colorectal adenocarcinoma ( n  = 330) registered from January 2015 to December 2019 (5-year duration) were selected for the study. Molecular analysis for BRAF . PIK3CA (exon 9 and 20) and RAS ( KRAS & NRAS ) was performed on representative formalin-fixed paraffin-embedded tissues by Sanger sequencing. Results were correlated with clinicopathological features. Patient overall survival (OS) was obtained using Kaplan-Meier method. Results  The study cohort was in the age range of 22 to 81 years (median age: 52 years) that included 202 males and 96 females (male: female ratio 2.1:1). BRAF V600E mutation was observed in three cases (1%), while 17 cases (5.7%) had mutations in the PIK3CA gene (exon 9 or exon 20). Mutation analysis for RAS gene ( KRAS & NRAS ) was observed among 42 (15.4%) cases with KRAS mutation and 11 (4%) cases were positive for NRAS mutations. Among RAS, KRAS G12D was the predominant mutation. Median OS with wild-type RAS was 46.6 months (95% confidence interval [CI]: 22.4-70.8), while for RAS mutated patients, it was 25.6 months (95% CI: 16.7-34.5), hazard ratio: 1.7 (95% CI: 1.1-2.7, p  = 0.025). Conclusion  This study evaluated the prevalence of BRAF, PIK3CA and RAS mutations in the Indian cohort and its impact on clinical behavior. There was lower incidence of BRAF mutations in this cohort and PIK3CA mutation (single) did not impact survival of the patients.
    Keywords:  BRAF; India; PIK3CA; RAS; colorectal cancer (CRC)
    DOI:  https://doi.org/10.1055/s-0041-1740244
  8. Clin Cancer Res. 2023 Jan 10. pii: CCR-22-3411. [Epub ahead of print]
    Alpelisib Efficacy Without Cherry-PI3King Mutations.
    Steven Tau, Todd W Miller.
      The PI3K inhibitor alpelisib is clinically approved for the treatment of metastatic ER+ breast cancers harboring hotspot mutations in PIK3CA, which encodes a subunit of PI3K. Prospective clinical trial results demonstrated benefit from alpelisib for the treatment of advanced ER+ breast cancers harboring PIK3CA mutations in the hotspots of exons 7, 9, and 20. However, 20% of PIK3CA mutations occur in non-hotspot regions. A recent article demonstrated that patients with cancers bearing non-hotspot PIK3CA mutations also derived benefit from alpelisib, which will inform clinical decision-making moving forward.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3411
  9. Gastroenterol Rep (Oxf). 2023 ;11 goac083
    Targeting KRAS G12C mutations in colorectal cancer.
    Ming-He Zhao, Ai-Wen Wu.
      With the advent of Kirsten rat sarcoma viral oncogene homologue G12C (KRAS G12C) inhibitors, RAS is no longer considered undruggable. For the suppression of RAS, new therapeutic approaches have been suggested. However, current clinical studies have indicated therapeutic resistance after short-lived tumour suppression. According to preclinical studies, this might be associated with acquired genetic alterations, reactivation of downstream pathways, and stimulation for upstream signalling. In this review, we aimed to summarize current approaches for combination therapy to alleviate resistance to KRAS G12C inhibitors in colorectal cancer with a focus on the mechanisms of therapeutic resistance. We also analysed the relationship between various mechanisms and therapeutic resistance.
    Keywords:  G12C; KRAS; colorectal neoplasms; combination therapy; drug resistance
    DOI:  https://doi.org/10.1093/gastro/goac083
  10. Cancers (Basel). 2022 Dec 20. pii: 17. [Epub ahead of print]15(1):
    Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer.
    Michal Grzmil, Fabius Wiesmann, Roger Schibli, Martin Behe.
      Radioligand therapy (RLT) represents an effective strategy to treat malignancy by cancer-selective delivery of radioactivity following systemic application. Despite recent therapeutic successes, cancer radioresistance and insufficient delivery of the radioactive ligands, as well as cytotoxicity to healthy organs, significantly impairs clinical efficacy. To improve disease management while minimizing toxicity, in recent years, the combination of RLT with molecular targeted therapies against cancer signaling networks showed encouraging outcomes. Characterization of the key deregulated oncogenic signaling pathways revealed their convergence to activate the mammalian target of rapamycin (mTOR), in which signaling plays an essential role in the regulation of cancer growth and survival. Therapeutic interference with hyperactivated mTOR pathways was extensively studied and led to the development of mTOR inhibitors for clinical applications. In this review, we outline the regulation and oncogenic role of mTOR signaling, as well as recapitulate and discuss mTOR complex 1 (mTORC1) inhibition to improve the efficacy of RLT in cancer.
    Keywords:  PRRT; RLT; TRT; mTOR; mammalian target of rapamycin; radioligand therapy; radiosensitization; rapalogs; targeted radionuclide therapy
    DOI:  https://doi.org/10.3390/cancers15010017
  11. Cell Rep. 2022 Dec 28. pii: S2211-1247(22)01815-0. [Epub ahead of print]42(1): 111916
    The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region.
    Guanlan Fan, Fan Wang, Yurou Chen, Qian Zheng, Jie Xiong, Qiongying Lv, Kejia Wu, Jiaqiang Xiong, Lei Wei, Dongqing Li, Jiachen Zhang, Wei Zhang, Feng Li.
      Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells' proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain.
    Keywords:  Akt signaling pathway; CP: Cancer; CP: Molecular biology; targeted therapies; tumour-suppressor protein OTUD1
    DOI:  https://doi.org/10.1016/j.celrep.2022.111916
  12. Sci Rep. 2023 Jan 12. 13(1): 632
    PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia.
    Maja Louise Arendt, Sharadha Sakthikumar, Malin Melin, Ingegerd Elvers, Patricio Rivera, Majbritt Larsen, Sara Saellström, Frode Lingaas, Henrik Rönnberg, Kerstin Lindblad-Toh.
      Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.
    DOI:  https://doi.org/10.1038/s41598-023-27664-7
  13. Nature. 2023 Jan 11.
    An atlas of substrate specificities for the human serine/threonine kinome.
    Jared L Johnson, Tomer M Yaron, Emily M Huntsman, Alexander Kerelsky, Junho Song, Amit Regev, Ting-Yu Lin, Katarina Liberatore, Daniel M Cizin, Benjamin M Cohen, Neil Vasan, Yilun Ma, Konstantin Krismer, Jaylissa Torres Robles, Bert van de Kooij, Anne E van Vlimmeren, Nicole Andrée-Busch, Norbert F Käufer, Maxim V Dorovkov, Alexey G Ryazanov, Yuichiro Takagi, Edward R Kastenhuber, Marcus D Goncalves, Benjamin D Hopkins, Olivier Elemento, Dylan J Taatjes, Alexandre Maucuer, Akio Yamashita, Alexei Degterev, Mohamed Uduman, Jingyi Lu, Sean D Landry, Bin Zhang, Ian Cossentino, Rune Linding, John Blenis, Peter V Hornbeck, Benjamin E Turk, Michael B Yaffe, Lewis C Cantley.
      Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.
    DOI:  https://doi.org/10.1038/s41586-022-05575-3
  14. Mol Cancer Ther. 2023 Jan 09. pii: MCT-22-0306. [Epub ahead of print]
    Discovery of a novel ATP-competitive MEK inhibitor DS03090629 that overcomes resistance conferred by BRAF overexpression in BRAF-mutated melanoma.
    Kohei Takano, Yoichi Munehira, Mana Hatanaka, Ryo Murakami, Yoshihiro Shibata, Takeshi Shida, Kosuke Takeuchi, Sho Takechi, Toshiki Tabata, Takashi Shimada, Shuhei Kishikawa, Yumi Matsui, Osamu Ubukata, Takahiko Seki, Yasuyuki Kaneta.
      Melanoma patients with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the mitogen-activated protein kinase (MAPK) pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0306
  15. Sci Rep. 2023 Jan 06. 13(1): 287
    Transcriptional activity mediated by β-CATENIN and TCF/LEF family members is completely dispensable for survival and propagation of multiple human colorectal cancer cell lines.
    Janna Fröhlich, Katja Rose, Andreas Hecht.
      Unrestrained transcriptional activity of β-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10% of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) family members, or rather lose addiction to β-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or β-CATENIN expression. Survival of these cells and the ability to propagate them demonstrate their complete β-CATENIN- and TCF/LEF-independence. Nonetheless, one β-CATENIN-deficient cell line eventually became senescent, and absence of TCF/LEF proteins and β-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/β-CATENIN signaling in the healthy intestine. Despite this common phenotype, β-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between β-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, β-CATENIN and TCF7L2 independently control sizeable fractions of their target genes. The observed divergence of β-CATENIN and TCF7L2 transcriptional programs, and the finding that neither β-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.
    DOI:  https://doi.org/10.1038/s41598-022-27261-0
  16. Sci Adv. 2023 Jan 06. 9(1): eade9120
    Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
    Dennis J Hsu, Jenny Gao, Norihiro Yamaguchi, Alexandra Pinzaru, Qiushuang Wu, Nandan Mandayam, Maria Liberti, Søren Heissel, Hanan Alwaseem, Saeed Tavazoie, Sohail F Tavazoie.
      Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
    DOI:  https://doi.org/10.1126/sciadv.ade9120
  17. Sci Rep. 2023 Jan 10. 13(1): 518
    Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors.
    Kotaro Sakamoto, Yun Qi, Eijiro Miyako.
      Single amino acid mutations of Ras occur in 30% of human cancers. In particular, K-Ras(G12D) has been detected in the majority of intractable colorectal and pancreatic cancers. Although efforts to target K-Ras(G12D) are currently underway, no effective drugs are available. We previously found that the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 exhibits antitumor activity against syngeneic colon and orthotopic grafted pancreatic tumors; however, pristine KS-58 is difficult to handle because of low water solubility and it requires frequent administration to obtain sufficient antitumor activity. In this study, we used a nanoformulation of KS-58 prepared with the highly biocompatible surfactant Cremophor® EL (CrEL) to improve water solubility and reduce the dosing frequency. Nanoformulations of KS-58 with CrEL dramatically improved its water solubility and increased its stability. Weekly intravenous administration of KS-58 nanoparticles (NPs) suppressed the growth of CT26 and PANC-1 cell-derived tumors in vivo, and fluorescent bioimaging indicated that the NP-encapsulated near-infrared fluorescent probe indocyanine green selectively accumulated in the tumor and was safely excreted through the kidneys following intravenous injection. Histopathological analysis of CT26 tumors and Western blotting of PANC-1 tumors revealed that KS-58 NPs reduced ERK phosphorylation, a downstream signal of K-Ras(G12D). Our results suggest that KS-58 NPs represent a novel therapeutic agent for treating colorectal and pancreatic cancers.
    DOI:  https://doi.org/10.1038/s41598-023-27825-8
  18. Nat Chem Biol. 2023 Jan 12.
    SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.
    Xiaomei Zhu, Qunshu Su, Haiyuan Xie, Lizhi Song, Fan Yang, Dandan Zhang, Binghong Wang, Shixian Lin, Jun Huang, Mengjie Wu, Ting Liu.
      The cell-cycle checkpoint kinase WEE1 is emerging as a therapeutic target for cancer treatment. However, how its catalytic activity is regulated remains poorly understood, and reliable biomarkers for predicting response to WEE1 inhibitor remain to be identified. Here we identify an evolutionarily conserved segment surrounding its Lys177 residue that inhibits WEE1 activity through an intermolecular interaction with the catalytic kinase domain. Upon DNA damage, CHK1-dependent phosphorylation of WEE1 at Ser642 primes GCN5-mediated acetylation at Lys177, resulting in dissociation of the inhibitory segment from the kinase domain and subsequent activation of WEE1 and cell-cycle checkpoints. Conversely, SIRT1 associates with and deacetylates WEE1, which maintains it in an inactive state. Consequently, SIRT1 deficiency induces WEE1 hyperacetylation and activation, rendering cancer cells resistant to WEE1 inhibition. These results suggest that SIRT1 expression level and abundance of WEE1 Lys177 acetylation in tumor cells can serve as useful biomarkers for predicting WEE1 inhibitor sensitivity or resistance.
    DOI:  https://doi.org/10.1038/s41589-022-01240-y
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