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Cited by 123Endoplasmic Reticulum Stress and DiseaseProtein Kinase Regulation and GTPase SignalingMelanoma and MAPK Pathways

Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors

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Lv, Xiangdong, Lu, Xuan, Cao, Jin, Luo, Qin, Ding, Yao, Peng, Fanglue, Pataer, Apar, Lu, Dong +31 more·2023·Science
DOI 10.1126/science.abn4180PMC PMC10720158
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Abstract

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress–independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal–regulated kinase (ERK)–dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

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  • Sotorasib promoted SEL1L-dependent ubiquitination of IRE1α, and cells that developed resistance to KRAS inhibition reactivated IRE1α via a MEK/ERK-independent, PI3K/AKT-dependent mechanism to restore normal proteostasis.

    “Sotorasib promoted the SEL1L-dependent ubiquitination of IRE1α, and cells that developed resistance to KRAS inhibition reactivated IRE1α via a MEK/ERK-independent, PI3K/AKT-dependent mechanism to functionally restore normal proteostasis.”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [82]

    The section “MAPK Promotes IRE1α Protein Stability” reports that sotorasib increased IRE1α ubiquitination and that SEL1L knockdown reduced this effect. The section “Multiple Pathways Converge to Reactivate IRE1α” reports restoration of IRE1α and proteostasis in KRAS-inhibitor-resistant cells, but not by a MEK/ERK-independent, PI3K/AKT-dependent mechanism: ERK and AKT can each sustain IRE1α, and suppressing both was required to blunt its reactivation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Oncogenic KRAS regulates protein quality control in KRAS-mutant tumor cells.

    “Oncogenic KRAS regulates protein quality control in KRAS-mutant tumor cells [161].”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [161]

  • Inhibition of oncogenic KRAS disrupts proteostasis.

    “while inhibition of oncogenic KRAS disrupted the proteostasis and triggered proteotoxic stresses”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [161]

  • Protein homeostasis (proteostasis) is crucial for the growth of tumor cells.

    “Protein homeostasis, or proteostasis, is crucial for the growth of tumor cells [161].”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [161]

  • Surviving cells after oncogenic KRAS inhibition rewire the proteostasis network by activating IRE1α.

    “surviving cells were able to rewire the proteostasis network by activating inositol-requiring enzyme 1α (IRE1α) [161].”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [161]

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Research works printed but not linked: 68

  1. [1]Scheidig AJ, Burmester C, Goody RS, The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins. Structure 7, 1311– 1324 (1999). 10574788
  2. [2]Scheffzek K., The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333– 338 (1997). 9219684
  3. [3]Bollag G, McCormick F, Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 351, 576– 579 (1991). 1904555
  4. [5]McGrath JP, Capon DJ, Goeddel DV, Levinson AD, Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310, 644– 649 (1984). 6147754
  5. [6]Downward J, Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11– 22 (2003). 12509763
  6. [9]Encarnación-Rosado J, Kimmelman AC, Harnessing metabolic dependencies in pancreatic cancers. Nat. Rev. Gastroenterol. Hepatol. 18, 482– 492 (2021). 33742165 PMC8249349
  7. [10]Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D, RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 11, 761– 774 (2011). 21993244 PMC3632399
  8. [15]Hong DS, KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N. Engl. J. Med. 383, 1207– 1217 (2020). 32955176 PMC7571518
  9. [17]Akhave NS, Biter AB, Hong DS, Mechanisms of Resistance to KRAS(G12C)-Targeted Therapy. Cancer Discov. 11, 1345– 1352 (2021). 33820777 PMC8178176
  10. [18]Awad MM, Acquired Resistance to KRASG12C Inhibition in Cancer. N. Engl. J. Med. 384, 2382– 2393 (2021). 34161704 PMC8864540
  11. [25]Xue JY, Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577, 421– 425 (2020). 31915379 PMC7308074
  12. [27]Brown WS, Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer. Cell Rep Med 1, 100131 (2020). PMC7691443 33294856
  13. [29]Suzuki S., KRAS Inhibitor Resistance in MET-Amplified KRAS (G12C) Non-Small Cell Lung Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms. Clin. Cancer Res. 27, 5697– 5707 (2021). 34365406
  14. [30]Punekar SR, Velcheti V, Neel BG, Wong KK, The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol. 19, 637– 655 (2022). 36028717 PMC9412785
  15. [31]Longo DL, Rosen N, Targeting Oncogenic RAS Protein. N. Engl. J. Med. 387, 184– 186 (2022). 35830646
  16. [33]Fedele C., SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J. Exp. Med. 218, (2021). PMC7549316 33045063
  17. [34]Ho CSL, HER2 mediates clinical resistance to the KRAS(G12C) inhibitor sotorasib, which is overcome by co-targeting SHP2. Eur. J. Cancer 159, 16– 23 (2021). 34715459
  18. [35]Ryan MB, KRAS(G12C)-independent feedback activation of wild-type RAS constrains KRAS(G12C) inhibitor efficacy. Cell reports 39, 110993 (2022). PMC9809542 35732135
  19. [36]Sattler M, Mohanty A, Kulkarni P, Salgia R, Precision oncology provides opportunities for targeting KRAS-inhibitor resistance. Trends in Cancer 9, 42– 54 (2023). 36751115
  20. [39]Fisher GH, Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249– 3262 (2001). 11751631 PMC312852
  21. [40]Joshi S., Adapting to stress - chaperome networks in cancer. Nat. Rev. Cancer 18, 562– 575 (2018). 29795326 PMC6108944
  22. [41]Chen X, Cubillos-Ruiz JR, Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer 21, 71– 88 (2021). 33214692 PMC7927882
  23. [43]Walter P, Ron D, The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081– 1086 (2011). 22116877
  24. [45]Almanza A., Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J 286, 241– 278 (2019). 30027602 PMC7379631
  25. [46]Gomez-Pastor R, Burchfiel ET, Thiele DJ, Regulation of heat shock transcription factors and their roles in physiology and disease. Nature reviews Molecular cell biology 19, 4– 19 (2018). 28852220 PMC5794010
  26. [47]Tang Z., MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell 160, 729– 744 (2015). 25679764 PMC4564124
  27. [48]Clarke HJ, Chambers JE, Liniker E, Marciniak SJ, Endoplasmic reticulum stress in malignancy. Cancer Cell 25, 563– 573 (2014). 24823636
  28. [49]Cox JS, Shamu CE, Walter P, Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73, 1197– 1206 (1993). 8513503
  29. [50]Morl K, Ma W, Gething M-J, Sambrook J, A transmembrane protein with a cdc2+ CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell 74, 743– 756 (1993). 8358794
  30. [51]Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K, XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881– 891 (2001). 11779464
  31. [52]Calfon M., IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92– 96 (2002). 11780124
  32. [53]Denoyelle C., Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat. Cell Biol. 8, 1053– 1063 (2006). 16964246
  33. [54]Sustic T., A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers. Genome Med. 10, 90 (2018). 30482246 PMC6258447
  34. [56]Nilsson MR, Techniques to study amyloid fibril formation in vitro. Methods 34, 151– 160 (2004). 15283924
  35. [57]Galves M, Rathi R, Prag G, Ashkenazi A, Ubiquitin signaling and degradation of aggregate-prone proteins. Trends Biochem. Sci. 44, 872– 884 (2019). 31079890
  36. [58]Klaips CL, Jayaraj GG, Hartl FU, Pathways of cellular proteostasis in aging and disease. J. Cell Biol. 217, 51– 63 (2017). 29127110 PMC5748993
  37. [59]Cortez L, Sim V, The therapeutic potential of chemical chaperones in protein folding diseases. Prion 8, 197– 202 (2014). 24818993 PMC4189890
  38. [60]Engin F., Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Sci. Transl. Med. 5, 211ra156 (2013). PMC4169117 24225943
  39. [61]Costa-Mattioli M, Walter P, The integrated stress response: From mechanism to disease. Science 368, eaat5314 (2020). PMC8997189 32327570
  40. [62]Guettouche T, Boellmann F, Lane WS, Voellmy R, Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem. 6, 4 (2005). 15760475 PMC1079796
  41. [63]Tirasophon W, Welihinda AA, Kaufman RJ, A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12, 1812– 1824 (1998). 9637683 PMC316900
  42. [64]Hollien J, Weissman JS, Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104– 107 (2006). 16825573
  43. [65]Lhomond S., Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol. Med. 10, e7929 (2018). 29311133 PMC5840541
  44. [70]Sun S., IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat. Cell Biol. 17, 1546– 1555 (2015). 26551274 PMC4670240
  45. [71]Brodsky JL, Cleaning up: ER-associated degradation to the rescue. Cell 151, 1163– 1167 (2012). 23217703 PMC3521611
  46. [72]Liu X., Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte beta-selection. Elife 10, e69975 (2021). PMC8315795 34240701
  47. [73]Xu L., Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions. Nat. Cell Biol. 22, 1162– 1169 (2020). 32958856 PMC7888538
  48. [74]Meyer H, Bug M, Bremer S, Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117– 123 (2012). 22298039
  49. [75]Anderson J, Daniel, Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell 28, 653– 665 (2015). 26555175 PMC4941640
  50. [76]Roskoski R Jr., ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66, 105– 143 (2012). 22569528
  51. [77]Satpathy S., A proteogenomic portrait of lung squamous cell carcinoma. Cell 184, 4348– 4371 e4340 (2021). 34358469 PMC8475722
  52. [78]You K., QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis. Science 371, eabb6896 (2021). PMC8315080 33384352
  53. [79]Liu CY, Xu Z, Kaufman RJ, Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha. J. Biol. Chem. 278, 17680– 17687 (2003). 12637535
  54. [80]Buscail L, Bournet B, Cordelier P, Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 17, 153– 168 (2020). 32005945
  55. [81]Tolcher AW, Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin. Cancer Res. 21, 739– 748 (2015). 25516890 PMC4335074
  56. [82]Chung V., Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. JAMA Oncol 3, 516– 522 (2017). 27978579 PMC5665683
  57. [83]Zhao N., Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J. Clin. Invest. 128, 1283– 1299 (2018). 29480818 PMC5873887
  58. [84]Le Reste PJ, Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo. Cancer Lett. 494, 73– 83 (2020). 32882336
  59. [85]Logue SE, Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nature communications 9, 3267 (2018). PMC6093931 30111846
  60. [88]Mahler HC, Friess W, Grauschopf U, Kiese S, Protein aggregation: pathways, induction factors and analysis. J. Pharm. Sci. 98, 2909– 2934 (2009). 18823031
  61. [90]Kim MP, Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat. Protoc. 4, 1670– 1680 (2009). 19876027 PMC4203372
  62. [91]Yan L., Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition. Cancer Res. 81, 4054– 4065 (2021). 34117030 PMC8338909
  63. [92]Cheng Z., Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res. 19, 1748– 1759 (2013). 23403638 PMC4172367
  64. [93]Sanjana NE, Shalem O, Zhang F, Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 11, 783– 784 (2014). 25075903 PMC4486245
  65. [94]Bankhead P., QuPath: Open source software for digital pathology image analysis. Sci. Rep. 7, 1– 7 (2017). 29203879 PMC5715110
  66. [95]Wrighton KH, Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling. J. Biol. Chem. 281, 38365– 38375 (2006). 17035229
  67. [96]Cross BC, The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. U. S. A. 109, E869– 878 (2012). 22315414 PMC3326519
  68. [97]Vasaikar SV, Straub P, Wang J, Zhang B, LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 46, D956– D963 (2018). 29136207 PMC5753188

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Authors
Lv, X., Lu, X., Cao, J., Luo, Q., Ding, Y., Peng, F., Pataer, A., Lu, D., Han, D., Malmberg, E., Chan, D. W., Wang, X., Savage, S. R., Mao, S., Yu, J., Peng, F., Yan, L., Meng, H., Maneix, L., Han, Y., Chen, Y., Yao, W., Chang, E. C., Catic, A., Lin, X., Miles, G., Huang, P., Sun, Z., Burt, B., Wang, H., Wang, J., Yao, Q. C., Zhang, B., Roth, J. A., O’Malley, B. W., Ellis, M. J., Rimawi, M. F., Ying, H., & Chen, X.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Corresponding author
  • Lv, Xiangdong
  • Lu, Xuan
  • Cao, Jin
  • Ying, Haoqiang
  • Chen, Xi
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-09-08
Volume
381
Issue
6662
Pages
eabn4180-eabn4180
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abn4180
PMC
PMC10720158
OpenAlex
W4386523015
Cited by
123
References
28
Citations by year
2026: 35 · 2025: 52 · 2024: 30 · 2023: 6
FWCI
17.80
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • U.S. Department of Defense (W81XWH1910524)
  • Cancer Prevention and Research Institute of Texas (DK56338, P50CA186784, CPRIT-RP180672, RR160027, RP150578, RP230285, RR140038, RP180672, CA125123, RR024574, RP160283)
  • National Institutes of Health (CPRIT-RP180672, 1s10od025251-01, 1s10od028671-01, RP150578, DK56338, T32DK60445, CA125123, CA126752)
  • National Heart, Lung, and Blood Institute (R01HL146642)
  • National Cancer Institute (R01CA196941, P50CA186784, U24CA210954, R21CA215591, R01CA195651, U54CA224065, R37CA228304, R01CA270240, R37CA248478, P01CA117969, P30CA125123, U54CA224081, R37CA272744, P50CA126752, R01CA214793)
  • National Institute of General Medical Sciences (R01GM142143, R01GM130838)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115454, T32DK060445, P30DK056338)
  • National Institute of Neurological Disorders and Stroke (R01NS117668)
  • National Center for Research Resources (S10RR024574)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD100535, R01HD008188, R01HD007857)
  • Congressionally Directed Medical Research Programs (W81XWH-19-1-0035, W81XWH-19-1-0524)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
KRAS inhibitors, drug resistance, proteostasis, IRE1α, unfolded protein response, heat shock response, ERK1/2 phosphorylation, Akt signaling, oncogenic KRAS, endoplasmic reticulum stress, tumor resistance mechanisms
MeSH terms
Proteostasis, Heat Shock Transcription Factors, Antineoplastic Agents, Endoribonucleases, Enzyme Inhibitors, Humans, Neoplasms, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases

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