E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Drug Resistance, Neoplasm
/ drug effects
Drug Therapy, Combination
Gastrointestinal Neoplasms
/ drug therapy
Gastrointestinal Stromal Tumors
/ drug therapy
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Imatinib Mesylate
/ pharmacology
Mice
Muscle Proteins
/ antagonists & inhibitors
Proto-Oncogene Proteins c-kit
/ antagonists & inhibitors
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
SKP Cullin F-Box Protein Ligases
/ antagonists & inhibitors
Sulfides
/ pharmacology
Sulfonamides
/ pharmacology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
22
07
2021
accepted:
28
09
2021
revised:
20
09
2021
pubmed:
9
10
2021
medline:
4
1
2022
entrez:
8
10
2021
Statut:
ppublish
Résumé
KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients' samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)-the main effector of muscular atrophy in cachexia-resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.
Identifiants
pubmed: 34621020
doi: 10.1038/s41388-021-02049-0
pii: 10.1038/s41388-021-02049-0
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Muscle Proteins
0
Pyrazoles
0
Pyrimidines
0
Sulfides
0
Sulfonamides
0
Imatinib Mesylate
8A1O1M485B
FBXO32 protein, human
EC 2.3.2.27
SKP Cullin F-Box Protein Ligases
EC 2.3.2.27
KIT protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
TAK-243
V9GGV0YCDI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6614-6626Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Cancer Netw. 2010;8:S1–41.
doi: 10.6004/jnccn.2010.0116
Serrano C, George S. Gastrointestinal stromal tumor: challenges and opportunities for a new decade. Clin Cancer Res. 2020;26:5078–85. https://doi.org/10.1158/1078-0432.CCR-20-1706
doi: 10.1158/1078-0432.CCR-20-1706
pubmed: 32601076
Taylor BS, Barretina J, Maki RG, Antonescu CR, Singer S, Ladanyi M. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011;11:541–57. https://doi.org/10.1038/nrc3087
doi: 10.1038/nrc3087
pubmed: 21753790
pmcid: 3361898
Wang Y, Marino-Enriquez A, Bennett RR, Zhu M, Shen Y, Eilers G, et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet. 2014;46:601–6. https://doi.org/10.1038/ng.2974
doi: 10.1038/ng.2974
pubmed: 24793134
pmcid: 4225780
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.
doi: 10.1126/science.279.5350.577
pubmed: 9438854
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10. https://doi.org/10.1126/science.1079666
doi: 10.1126/science.1079666
pubmed: 12522257
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl J Med. 2002;347:472–80. https://doi.org/10.1056/NEJMoa020461
doi: 10.1056/NEJMoa020461
pubmed: 12181401
Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74. https://doi.org/10.1002/path.2382
doi: 10.1002/path.2382
pubmed: 18623623
pmcid: 2693040
Serrano C, Marino-Enriquez A, Tao DL, Ketzer J, Eilers G, Zhu M, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J cancer. 2019;120:612–20. https://doi.org/10.1038/s41416-019-0389-6
doi: 10.1038/s41416-019-0389-6
pubmed: 30792533
pmcid: 6462042
Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–74. https://doi.org/10.1200/JCO.2006.06.2265
doi: 10.1200/JCO.2006.06.2265
pubmed: 16954519
Liu Y, Perdreau SA, Chatterjee P, Wang L, Kuan SF, Duensing A. Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis. Cancer Res. 2008;68:9015–23. https://doi.org/10.1158/0008-5472.CAN-08-1935
doi: 10.1158/0008-5472.CAN-08-1935
pubmed: 18974147
Boichuk S, Parry JA, Makielski KR, Litovchick L, Baron JL, Zewe JP, et al. The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res. 2013;73:5120–9. https://doi.org/10.1158/0008-5472.CAN-13-0579
doi: 10.1158/0008-5472.CAN-13-0579
pubmed: 23786773
Cohen NA, Zeng S, Seifert AM, Kim TS, Sorenson EC, Greer JB, et al. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Res. 2015;75:2061–70. https://doi.org/10.1158/0008-5472.CAN-14-2564
doi: 10.1158/0008-5472.CAN-14-2564
pubmed: 25836719
pmcid: 4467991
Li F, Huynh H, Li X, Ruddy DA, Wang Y, Ong R, et al. FGFR-mediated reactivation of MAPK signaling attenuates antitumor effects of imatinib in gastrointestinal stromal tumors. Cancer Discov. 2015;5:438–51. https://doi.org/10.1158/2159-8290.CD-14-0763
doi: 10.1158/2159-8290.CD-14-0763
pubmed: 25673643
Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene. 2004;23:3999–4006. https://doi.org/10.1038/sj.onc.1207525
doi: 10.1038/sj.onc.1207525
pubmed: 15007386
Bauer S, Duensing A, Demetri GD, Fletcher JA. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 2007;26:7560–8. https://doi.org/10.1038/sj.onc.1210558
doi: 10.1038/sj.onc.1210558
pubmed: 17546049
Zhu MJ, Ou WB, Fletcher CD, Cohen PS, Demetri GD, Fletcher JA. KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance. Oncogene. 2007;26:6386–95. https://doi.org/10.1038/sj.onc.1210464
doi: 10.1038/sj.onc.1210464
pubmed: 17452978
Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010;467:849–53. https://doi.org/10.1038/nature09409
doi: 10.1038/nature09409
pubmed: 20927104
pmcid: 2955195
Bosbach B, Rossi F, Yozgat Y, Loo J, Zhang JQ, Berrozpe G, et al. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci USA. 2017;114:E8448–E57. https://doi.org/10.1073/pnas.1711449114
doi: 10.1073/pnas.1711449114
pubmed: 28923937
pmcid: 5635919
Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA. 2001;98:14440–5. https://doi.org/10.1073/pnas.251541198
doi: 10.1073/pnas.251541198
pubmed: 11717410
pmcid: 64700
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117:399–412. https://doi.org/10.1016/s0092-8674(04)00400-3
doi: 10.1016/s0092-8674(04)00400-3
pubmed: 15109499
pmcid: 3619734
Bardia A, Gounder M, Rodon J, Janku F, Lolkema MP, Stephenson JJ, et al. Phase Ib study of combination therapy with MEK inhibitor binimetinib and phosphatidylinositol 3-kinase inhibitor buparlisib in patients with advanced solid tumors with RAS/RAF alterations. Oncologist. 2020;25:e160–e9. https://doi.org/10.1634/theoncologist.2019-0297
doi: 10.1634/theoncologist.2019-0297
pubmed: 31395751
Frolov A, Chahwan S, Ochs M, Arnoletti JP, Pan ZZ, Favorova O, et al. Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. Mol Cancer Ther. 2003;2:699–709.
pubmed: 12939459
Chou JL, Su HY, Chen LY, Liao YP, Hartman-Frey C, Lai YH, et al. Promoter hypermethylation of FBXO32, a novel TGF-beta/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer. Lab Investig. 2010;90:414–25. https://doi.org/10.1038/labinvest.2009.138
doi: 10.1038/labinvest.2009.138
pubmed: 20065949
Ciarapica R, De Salvo M, Carcarino E, Bracaglia G, Adesso L, Leoncini PP, et al. The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx). Oncogene. 2014;33:4173–84. https://doi.org/10.1038/onc.2013.471
doi: 10.1038/onc.2013.471
pubmed: 24213577
Zhou H, Liu Y, Zhu R, Ding F, Wan Y, Li Y, et al. FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation. Oncogene. 2017;36:3312–21. https://doi.org/10.1038/onc.2016.479
doi: 10.1038/onc.2016.479
pubmed: 28068319
pmcid: 5926769
van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol cell Biol. 2007;8:440–50. https://doi.org/10.1038/nrm2190
doi: 10.1038/nrm2190
pubmed: 17522590
Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48. https://doi.org/10.1038/ncb1676
doi: 10.1038/ncb1676
pubmed: 18204439
pmcid: 2376808
Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, et al. beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18:892–901. https://doi.org/10.1038/nm.2772
doi: 10.1038/nm.2772
pubmed: 22610277
Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M, et al. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem. 2005;280:20814–23. https://doi.org/10.1074/jbc.M500528200
doi: 10.1074/jbc.M500528200
pubmed: 15781459
Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004;5:739–51. https://doi.org/10.1038/nrm1471
doi: 10.1038/nrm1471
pubmed: 15340381
Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012;19:1074–80. https://doi.org/10.1245/s10434-011-2190-5
doi: 10.1245/s10434-011-2190-5
pubmed: 22203182
Hyer ML, Milhollen MA, Ciavarri J, Fleming P, Traore T, Sappal D, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med. 2018;24:186–93. https://doi.org/10.1038/nm.4474
doi: 10.1038/nm.4474
pubmed: 29334375
Jin J, Li X, Gygi SP, Harper JW. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature. 2007;447:1135–8. https://doi.org/10.1038/nature05902
doi: 10.1038/nature05902
pubmed: 17597759
Hemming ML, Lawlor MA, Zeid R, Lesluyes T, Fletcher JA, Raut CP, et al. Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc Natl Acad Sci USA. 2018;115:E5746–E55. https://doi.org/10.1073/pnas.1802079115
doi: 10.1073/pnas.1802079115
pubmed: 29866822
pmcid: 6016782
Grunewald S, Klug LR, Muhlenberg T, Lategahn J, Falkenhorst J, Town A, et al. Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov. 2020. https://doi.org/10.1158/2159-8290.CD-20-0487
Serrano C, Leal A, Kuang Y, Morgan JA, Barysauskas CM, Phallen J, et al. Phase I study of rapid alternation of sunitinib and regorafenib for the treatment of tyrosine kinase inhibitor refractory gastrointestinal stromal tumors. Clin Cancer Res. 2019;25:7287–93. https://doi.org/10.1158/1078-0432.CCR-19-2150
doi: 10.1158/1078-0432.CCR-19-2150
pubmed: 31471313
Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9. https://doi.org/10.1200/JCO.2007.15.7461
doi: 10.1200/JCO.2007.15.7461
pubmed: 18955458
pmcid: 2651076
Dolly SO, Wagner AJ, Bendell JC, Kindler HL, Krug LM, Seiwert TY, et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2016;22:2874–84. https://doi.org/10.1158/1078-0432.CCR-15-2225
doi: 10.1158/1078-0432.CCR-15-2225
pubmed: 26787751
pmcid: 4876928
Ran L, Chen Y, Sher J, Wong EWP, Murphy D, Zhang JQ, et al. FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor. Cancer Discov. 2018;8:234–51. https://doi.org/10.1158/2159-8290.CD-17-0468
doi: 10.1158/2159-8290.CD-17-0468
pubmed: 29162563
Tintignac LA, Lagirand J, Batonnet S, Sirri V, Leibovitch MP, Leibovitch SA. Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase. J Biol Chem. 2005;280:2847–56. https://doi.org/10.1074/jbc.M411346200
doi: 10.1074/jbc.M411346200
pubmed: 15531760
Lagirand-Cantaloube J, Offner N, Csibi A, Leibovitch MP, Batonnet-Pichon S, Tintignac LA, et al. The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy. EMBO J. 2008;27:1266–76. https://doi.org/10.1038/emboj.2008.52
doi: 10.1038/emboj.2008.52
pubmed: 18354498
pmcid: 2367397
Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D, et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci USA. 2010;107:14333–8. https://doi.org/10.1073/pnas.1000248107
doi: 10.1073/pnas.1000248107
pubmed: 20660757
pmcid: 2922542
Garcia-Valverde A, Rosell J, Serna G, Valverde C, Carles J, Nuciforo P, et al. Preclinical activity of PI3K inhibitor copanlisib in gastrointestinal stromal tumor. Mol Cancer Ther. 2020;19:1289–97. https://doi.org/10.1158/1535-7163.MCT-19-1069
doi: 10.1158/1535-7163.MCT-19-1069
pubmed: 32371592
Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, et al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014;20:5745–55. https://doi.org/10.1158/1078-0432.CCR-14-1397
doi: 10.1158/1078-0432.CCR-14-1397
pubmed: 25239608
pmcid: 4233175
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82. https://doi.org/10.1038/nmeth.2019
doi: 10.1038/nmeth.2019
pubmed: 22743772
Maurel J, Lopez-Pousa A, Calabuig S, Bague S, Del Muro XG, Sanjuan X, et al. Phosphorylated-insulin growth factor I receptor (p-IGF1R) and metalloproteinase-3 (MMP3) expression in advanced gastrointestinal stromal tumors (GIST). A GEIS 19 study. Clin Sarcoma Res. 2016;6:10 https://doi.org/10.1186/s13569-016-0050-6
doi: 10.1186/s13569-016-0050-6
pubmed: 27358721
pmcid: 4926286
Pascual-Reguant L, Blanco E, Galan S, Le Dily F, Cuartero Y, Serra-Bardenys G, et al. Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains. Nat Commun. 2018;9:3420 https://doi.org/10.1038/s41467-018-05912-z
doi: 10.1038/s41467-018-05912-z
pubmed: 30143639
pmcid: 6109041
Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, et al. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Investig. 2019;129:1863–77. https://doi.org/10.1172/JCI124108
doi: 10.1172/JCI124108
pubmed: 30762585
pmcid: 6486334
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47 https://doi.org/10.1093/nar/gkv007
doi: 10.1093/nar/gkv007
pubmed: 25605792
pmcid: 4402510