中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 12
Dec.  2022
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Article Contents

Role of KRAS mutation in metabolism of pancreatic ductal adenocarcinoma

DOI: 10.3969/j.issn.1001-5256.2022.12.043
Research funding:

National Science Foundation of China (81871997);

National Science Foundation of China (82170624)

More Information
  • Corresponding author: WU Jian, jian.wu@fudan.edu.cn (ORCID: 0000-0001-9933-7364)
  • Received Date: 2022-05-24
  • Accepted Date: 2022-08-10
  • Published Date: 2022-12-20
  • Pancreatic cancer is a malignant tumor with high fatality rate and poor prognosis, and gene mutations involved in tumor metabolism are considered as the basis of its progression and poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is reported that KRAS mutations are detected in 86% of PDAC patients. As a molecular switch in the upstream of various signaling pathways and transcription factors, KRAS plays an important role in the regulation of tumor cell metabolism. KRAS mutations may affect the metabolic reprogramming of nutrients and energy, macropinocytosis, and autophagy, regulate the interaction between components in tumor microenvironment, and maintain the survival and proliferation of cancer cells. At present, KRAS-targeting therapies for PDAC still remain in an experimental stage, and further clinical studies are needed to determine whether they can be safely applied in treatment.

     

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  • [1]
    SIEGEL RL, MILLER KD, FUCHS HE, et al. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. DOI: 10.3322/caac.21654.
    [2]
    BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
    [3]
    HUANG L, JANSEN L, BALAVARCA Y, et al. Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations[J]. Gut, 2019, 68(1): 130-139. DOI: 10.1136/gutjnl-2017-314828.
    [4]
    HENRIKSEN A, DYHL-POLK A, CHEN I, et al. Checkpoint inhibitors in pancreatic cancer[J]. Cancer Treat Rev, 2019, 78: 17-30. DOI: 10.1016/j.ctrv.2019.06.005.
    [5]
    INDINI A, RIJAVEC E, GHIDINI M, et al. Targeting KRAS in solid tumors: Current challenges and future opportunities of novel KRAS inhibitors[J]. Pharmaceutics, 2021, 13(5): 653. DOI: 10.3390/pharmaceutics13050653.
    [6]
    HOSEIN AN, BREKKEN RA, MAITRA A. Pancreatic cancer stroma: an update on therapeutic targeting strategies[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(8): 487-505. DOI: 10.1038/s41575-020-0300-1.
    [7]
    SUN H, ZHANG B, LI H. The Roles of frequently mutated genes of pancreatic cancer in regulation of tumor microenvironment[J]. Technol Cancer Res Treat, 2020, 19: 1533033820920969. DOI: 10.1177/1533033820920969.
    [8]
    HOLLINSHEAD K, PARKER SJ, EAPEN VV, et al. Respiratory supercomplexes promote mitochondrial efficiency and growth in severely hypoxic pancreatic cancer[J]. Cell Rep, 2020, 33(1): 108231. DOI: 10.1016/j.celrep.2020.108231.
    [9]
    DEY P, LI J, ZHANG J, et al. Oncogenic KRAS-Driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment[J]. Cancer Discov, 2020, 10(4): 608-625. DOI: 10.1158/2159-8290.CD-19-0297.
    [10]
    BUSCAIL L, BOURNET B, CORDELIER P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(3): 153-168. DOI: 10.1038/s41575-019-0245-4.
    [11]
    ENCARNACIÓN-ROSADO J, KIMMELMAN AC. Harnessing metabolic dependencies in pancreatic cancers[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(7): 482-492. DOI: 10.1038/s41575-021-00431-7.
    [12]
    NAGDAS S, KASHATUS JA, NASCIMENTO A, et al. Drp1 promotes KRas-driven metabolic changes to drive pancreatic tumor growth[J]. Cell Rep, 2019, 28(7): 1845-1859.e5. DOI: 10.1016/j.celrep.2019.07.031.
    [13]
    HOU P, KAPOOR A, ZHANG Q, et al. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer[J]. Cancer Discov, 2020, 10(7): 1058-1077. DOI: 10.1158/2159-8290.CD-19-0597.
    [14]
    SANTANA-CODINA N, ROETH AA, ZHANG Y, et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis[J]. Nat Commun, 2018, 9(1): 4945. DOI: 10.1038/s41467-018-07472-8.
    [15]
    LI X, JIANG Y, MEISENHELDER J, et al. Mitochondria-translocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis[J]. Mol Cell, 2016, 61(5): 705-719. DOI: 10.1016/j.molcel.2016.02.009.
    [16]
    ROZEVELD CN, JOHNSON KM, ZHANG L, et al. KRAS controls pancreatic cancer cell lipid metabolism and invasive potential through the lipase HSL[J]. Cancer Res, 2020, 80(22): 4932-4945. DOI: 10.1158/0008-5472.CAN-20-1255.
    [17]
    ROSSI SEBASTIANO M, POZZATO C, SALIAKOURA M, et al. ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression[J]. Sci Adv, 2020, 6(44): eabb9200. DOI: 10.1126/sciadv.abb9200.
    [18]
    ROSSI SEBASTIANO M, KONSTANTINIDOU G. Targeting long chain Acyl-CoA synthetases for cancer therapy[J]. Int J Mol Sci, 2019, 20(15): 3624. DOI: 10.3390/ijms20153624.
    [19]
    SALIAKOURA M, SEBASTIANO MR, NIKDIMA I, et al. Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy[J]. J Exp Clin Cancer Res, 2022, 41(1): 16. DOI: 10.1186/s13046-021-02231-y.
    [20]
    WANG YP, ZHOU W, WANG J, et al. Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer[J]. Mol Cell, 2016, 64(4): 673-687. DOI: 10.1016/j.molcel.2016.09.028.
    [21]
    RAHO S, CAPOBIANCO L, MALIVINDI R, et al. KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth[J]. Nat Metab, 2020, 2(12): 1373-1381. DOI: 10.1038/s42255-020-00315-1.
    [22]
    ZHANG Y, COMMISSO C. Macropinocytosis in cancer: A complex signaling network[J]. Trends Cancer, 2019, 5(6): 332-334. DOI: 10.1016/j.trecan.2019.04.002.
    [23]
    RAMIREZ C, HAUSER AD, VUCIC EA, et al. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis[J]. Nature, 2019, 576(7787): 477-481. DOI: 10.1038/s41586-019-1831-x.
    [24]
    KINSEY CG, CAMOLOTTO SA, BOESPFLUG AM, et al. Publisher correction: Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers[J]. Nat Med, 2019, 25(5): 861. DOI: 10.1038/s41591-019-0433-3.
    [25]
    HUMPTON TJ, ALAGESAN B, DENICOLA GM, et al. Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer[J]. Cancer Discov, 2019, 9(9): 1268-1287. DOI: 10.1158/2159-8290.CD-18-1409.
    [26]
    YAMAMOTO K, VENIDA A, YANO J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I[J]. Nature, 2020, 581(7806): 100-105. DOI: 10.1038/s41586-020-2229-5.
    [27]
    POMMIER A, ANAPARTHY N, MEMOS N, et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases[J]. Science, 2018, 360(6394). DOI: 10.1126/science.aao4908.
    [28]
    DAI E, HAN L, LIU J, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein[J]. Autophagy, 2020, 16(11): 2069-2083. DOI: 10.1080/15548627.2020.1714209.
    [29]
    MONTERAN L, EREZ N. The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment[J]. Front Immunol, 2019, 10: 1835. DOI: 10.3389/fimmu.2019.01835.
    [30]
    HAMARSHEH S, GROβ O, BRUMMER T, et al. Immune modulatory effects of oncogenic KRAS in cancer[J]. Nat Commun, 2020, 11(1): 5439. DOI: 10.1038/s41467-020-19288-6.
    [31]
    WANG T, NOTTA F, NAVAB R, et al. Senescent carcinoma-associated fibroblasts upregulate IL8 to enhance prometastatic phenotypes[J]. Mol Cancer Res, 2017, 15(1): 3-14. DOI: 10.1158/1541-7786.MCR-16-0192.
    [32]
    HAFEZI S, SABER-AYAD M, ABDEL-RAHMAN WM. Highlights on the role of KRAS mutations in reshaping the microenvironment of pancreatic adenocarcinoma[J]. Int J Mol Sci, 2021, 22(19): 10219. DOI: 10.3390/ijms221910219.
    [33]
    NOLLMANN FI, RUESS DA. Targeting mutant KRAS in pancreatic cancer: Futile or promising?[J]. Biomedicines, 2020, 8(8): 281. DOI: 10.3390/biomedicines8080281.
    [34]
    CANON J, REX K, SAIKI AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity[J]. Nature, 2019, 575(7781): 217-223. DOI: 10.1038/s41586-019-1694-1.
    [35]
    HALLIN J, ENGSTROM LD, HARGIS L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients[J]. Cancer Discov, 2020, 10(1): 54-71. DOI: 10.1158/2159-8290.CD-19-1167.
    [36]
    HONG DS, FAKIH MG, STRICKLER JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors[J]. N Engl J Med, 2020, 383(13): 1207-1217. DOI: 10.1056/NEJMoa1917239.
    [37]
    JONCKHEERE N, VASSEUR R, VAN SEUNINGEN I. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting[J]. Crit Rev Oncol Hematol, 2017, 111: 7-19. DOI: 10.1016/j.critrevonc.2017.01.002.
    [38]
    DROSTEN M, BARBACID M. Targeting the MAPK pathway in KRAS-driven tumors[J]. Cancer Cell, 2020, 37(4): 543-550. DOI: 10.1016/j.ccell.2020.03.013.
    [39]
    TERRELL EM, MORRISON DK. Ras-mediated activation of the raf family kinases[J]. Cold Spring Harb Perspect Med, 2019, 9(1): a033746. DOI: 10.1101/cshperspect.a033746.
    [40]
    NAGASAKA M, POTUGARI B, NGUYEN A, et al. KRAS Inhibitors- yes but what next? Direct targeting of KRAS-vaccines, adoptive T cell therapy and beyond[J]. Cancer Treat Rev, 2021, 101: 102309. DOI: 10.1016/j.ctrv.2021.102309.
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