Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
13 10 2023
13 10 2023
Historique:
medline:
23
10
2023
pubmed:
13
10
2023
entrez:
13
10
2023
Statut:
ppublish
Résumé
Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.
Identifiants
pubmed: 37831779
doi: 10.1126/sciadv.ade3816
pmc: PMC10575592
doi:
Substances chimiques
Antiviral Agents
0
beta Catenin
0
KRAS protein, human
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eade3816Subventions
Organisme : NCI NIH HHS
ID : R01 CA218545
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247471
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM141290
Pays : United States
Références
PLoS Comput Biol. 2013;9(8):e1003118
pubmed: 23950696
Curr Oncol Rep. 2021 Feb 13;23(3):28
pubmed: 33582927
Front Genet. 2013 Aug 26;4:160
pubmed: 24032039
Mol Cell. 2012 Jun 29;46(6):871-83
pubmed: 22749400
Ann Oncol. 2021 Sep;32(9):1101-1110
pubmed: 34089836
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Biomolecules. 2021 Dec 21;12(1):
pubmed: 35053156
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Ann Oncol. 2013 Sep;24(9):2371-6
pubmed: 23723294
Cell Cycle. 2013 Jan 1;12(1):26-31
pubmed: 23255110
Bioinformatics. 2012 Aug 15;28(16):2184-5
pubmed: 22743226
Ann Oncol. 2015 Oct;26(10):2079-84
pubmed: 26209642
Expert Rev Mol Diagn. 2016 Jul;16(7):737-49
pubmed: 27139190
Bioinformatics. 2006 May 1;22(9):1036-46
pubmed: 16500937
N Engl J Med. 2020 Sep 24;383(13):1207-1217
pubmed: 32955176
Oncogene. 2019 Apr;38(16):2953-2966
pubmed: 30568222
N Engl J Med. 2021 Jun 24;384(25):2371-2381
pubmed: 34096690
Nature. 2020 Jan;577(7790):421-425
pubmed: 31915379
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Nature. 2018 Jan 24;553(7689):446-454
pubmed: 29364287
Trends Cancer. 2021 Apr;7(4):323-334
pubmed: 33622644
J Thorac Oncol. 2015 Mar;10(3):431-7
pubmed: 25415430
Clin Cancer Res. 2018 Jan 15;24(2):334-340
pubmed: 29089357
J Thorac Oncol. 2021 Aug;16(8):1321-1332
pubmed: 33971321
Cell Mol Life Sci. 2017 Sep;74(17):3245-3261
pubmed: 28597297
Comput Struct Biotechnol J. 2019 Dec 26;18:189-198
pubmed: 31988705
Mol Cell Proteomics. 2012 Jul;11(7):M111.014969
pubmed: 22389433
Pharmacol Rev. 1989 Jun;41(2):93-141
pubmed: 2692037
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13
pubmed: 26949479
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Cancers (Basel). 2021 Jan 05;13(1):
pubmed: 33466360
BMC Bioinformatics. 2016 Feb 03;17:58
pubmed: 26842848
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Methods Mol Biol. 2018;1711:351-398
pubmed: 29344898
J Cancer. 2019 Jan 29;10(4):821-828
pubmed: 30854087
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
PLoS Comput Biol. 2018 Sep 10;14(9):e1006458
pubmed: 30199525
Cancer Cell. 2021 Aug 9;39(8):1135-1149.e8
pubmed: 34143978
Cancers (Basel). 2021 May 21;13(11):
pubmed: 34064232
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Trends Cancer. 2018 Feb;4(2):110-118
pubmed: 29458961
Br J Cancer. 2020 Feb;122(4):465-472
pubmed: 31831859
Nat Methods. 2008 Jul;5(7):621-8
pubmed: 18516045
J Chem Inf Model. 2018 Feb 26;58(2):464-471
pubmed: 29320178
Sci Rep. 2020 Jul 20;10(1):11992
pubmed: 32686745
Nature. 2021 Nov;599(7886):679-683
pubmed: 34759319
Arzneimittelforschung. 1953 Jun;3(6):285-90
pubmed: 13081480
Cancer Res. 2018 Feb 1;78(3):593-602
pubmed: 29273632
N Engl J Med. 2021 Jun 24;384(25):2382-2393
pubmed: 34161704
Front Oncol. 2018 Mar 06;8:50
pubmed: 29560343
Ann Oncol. 2011 Jan;22(1):235-237
pubmed: 21169473
J Thorac Oncol. 2019 Apr;14(4):606-616
pubmed: 30605727
Front Oncol. 2019 Sep 25;9:953
pubmed: 31612108
Nat Rev Clin Oncol. 2021 Sep;18(9):541
pubmed: 34267362
Genomics Proteomics Bioinformatics. 2022 Jun;20(3):587-596
pubmed: 35085776
Mol Cancer. 2013 Sep 24;12(1):108
pubmed: 24063528
iScience. 2020 Aug 22;23(9):101496
pubmed: 32947124
Br J Cancer. 2016 Jul 26;115(3):346-53
pubmed: 27336603
Nature. 2012 Jan 18;481(7381):306-13
pubmed: 22258609
Cancer Discov. 2021 Aug;11(8):1913-1922
pubmed: 33824136
J Cell Biol. 2008 Jun 16;181(6):879-84
pubmed: 18541702
Sci Rep. 2019 Jun 27;9(1):9332
pubmed: 31249353