Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation

The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.

[1]  S. Moro,et al.  1,2,4-Amino-triazine derivatives as pyruvate dehydrogenase kinase inhibitors: Synthesis and pharmacological evaluation. , 2023, European journal of medicinal chemistry.

[2]  M. Fujishiro,et al.  Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment , 2022, Cancers.

[3]  H. Mano,et al.  Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy , 2022, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  Chun-Chi Chen,et al.  KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge , 2022, Cell discovery.

[5]  E. Giovannetti,et al.  A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells , 2021, Molecules.

[6]  P. Nurse,et al.  Core control principles of the eukaryotic cell cycle , 2021, Nature.

[7]  D. Tang,et al.  The KRAS-G12C inhibitor: activity and resistance , 2021, Cancer Gene Therapy.

[8]  Huan Yang,et al.  Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer , 2021, Clinical Cancer Research.

[9]  A. Jemal,et al.  Cancer Statistics, 2021 , 2021, CA: a cancer journal for clinicians.

[10]  P. Ettmayer,et al.  BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. , 2020, Cancer discovery.

[11]  P. Malfertheiner,et al.  Correlation of skin rash and overall survival in patients with pancreatic cancer treated with gemcitabine and erlotinib – results from a non-interventional multi-center study , 2020, BMC Cancer.

[12]  C. Scarlett,et al.  Small molecule inhibitors in pancreatic cancer. , 2020, RSC medicinal chemistry.

[13]  Nora S. Sanchez,et al.  Erratum: Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer (Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer (2014) 158(1) (185–197), (S0092867414007247), (10.1016/j.cell.2014.06.003)) , 2019 .

[14]  A. Trumpp,et al.  Survival of pancreatic cancer cells lacking KRAS function , 2017, Nature Communications.

[15]  P. Sidaway.  Pancreatic cancer: TCGA data reveal a highly heterogeneous disease , 2017, Nature Reviews Clinical Oncology.

[16]  A. Maitra,et al.  Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53 , 2016, Oncogene.

[17]  D. Weaver,et al.  Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy , 2016, Nature Medicine.

[18]  Rita T Lawlor,et al.  Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas , 2014, The Journal of pathology.

[19]  Joseph Rosenbluh,et al.  KRAS and YAP1 Converge to Regulate EMT and Tumor Survival , 2014, Cell.

[20]  A. Chambers,et al.  Cyclin A2, a novel regulator of EMT , 2014, Cellular and Molecular Life Sciences.

[21]  Awet G. Tecleab,et al.  Depletion of K-Ras promotes proteasome degradation of survivin , 2013, Cell cycle.

[22]  Lincoln D. Stein,et al.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes , 2012, Nature.

[23]  Jens T Siveke,et al.  EGF receptor is required for KRAS-induced pancreatic tumorigenesis. , 2012, Cancer cell.

[24]  M. Barbacid,et al.  EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[25]  T. Ohtsuka,et al.  Pancreatic Cancer Cells Enhance the Ability of Collagen Internalization during Epithelial–Mesenchymal Transition , 2012, PloS one.

[26]  B. Ancrile,et al.  Targeting eNOS in pancreatic cancer. , 2012, Cancer research.

[27]  Gerald C. Chu,et al.  Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism , 2012, Cell.

[28]  M. Malumbres,et al.  The anaphase-promoting complex/cyclosome (APC/C): cell-cycle-dependent and -independent functions. , 2010, Biochemical Society transactions.

[29]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[30]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[31]  R. Assoian,et al.  Transcriptional regulation of the cyclin D1 gene at a glance , 2008, Journal of Cell Science.

[32]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[33]  I. Prior,et al.  Ras isoform abundance and signalling in human cancer cell lines , 2008, Oncogene.

[34]  K. Lim,et al.  Tumour maintenance is mediated by eNOS , 2008, Nature.

[35]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[36]  S. Gygi,et al.  Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology , 2006, Nature Cell Biology.

[37]  J. Minna,et al.  Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. , 2006, Journal of the National Cancer Institute.

[38]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[39]  F. Brembeck,et al.  The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. , 2003, Cancer research.

[40]  D. Longnecker,et al.  Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. , 2003, Cancer research.

[41]  Andrew W. Stacey,et al.  Ras Is Active Throughout the Cell Cycle, but Is Able to Induce Cyclin D1 Only During G2 Phase , 2002, Cell cycle.

[42]  Weiyao Li,et al.  Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients , 2017, Pathology & Oncology Research.

[43]  F. McCormick,et al.  Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. , 2013, Cancer discovery.

[44]  M. Löhr,et al.  Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. , 2005, Neoplasia.