The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 03 2022
18 03 2022
Historique:
received:
19
02
2021
accepted:
11
02
2022
entrez:
19
3
2022
pubmed:
20
3
2022
medline:
6
4
2022
Statut:
epublish
Résumé
The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.
Identifiants
pubmed: 35304457
doi: 10.1038/s41467-022-28848-x
pii: 10.1038/s41467-022-28848-x
pmc: PMC8933489
doi:
Substances chimiques
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
RET protein, human
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1450Subventions
Organisme : NCI NIH HHS
ID : T32 CA160001
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207244
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA245069
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204749
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009512
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251591
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
Références
Nat Med. 2019 Sep;25(9):1422-1427
pubmed: 31406350
Nat Rev Cancer. 2017 May;17(5):318-332
pubmed: 28303906
Nat Biotechnol. 2016 Feb;34(2):155-63
pubmed: 26619011
Nat Genet. 2018 Aug;50(8):1189-1195
pubmed: 30013179
J Thorac Oncol. 2020 Jul;15(7):e124-e127
pubmed: 32593453
Cancer Discov. 2018 Oct;8(10):1227-1236
pubmed: 30093503
Clin Chem. 2020 Apr 1;66(4):616-618
pubmed: 32191320
Clin Cancer Res. 2017 Apr 15;23(8):1988-1997
pubmed: 27683183
JCO Precis Oncol. 2020 Oct 30;4:
pubmed: 33154983
Clin Cancer Res. 2020 Jun 1;26(11):2654-2663
pubmed: 31911548
N Engl J Med. 2020 Aug 27;383(9):813-824
pubmed: 32846060
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Nat Rev Clin Oncol. 2018 Dec;15(12):731-747
pubmed: 30333516
Bioinformatics. 2014 Apr 1;30(7):1015-6
pubmed: 24371154
Clin Cancer Res. 2021 Jan 1;27(1):34-42
pubmed: 33082208
Nucleic Acids Res. 2016 Sep 19;44(16):e131
pubmed: 27270079
Cancer Cell. 2018 Nov 12;34(5):852-862.e4
pubmed: 30393068
Sci Transl Med. 2015 Apr 15;7(283):283ra54
pubmed: 25877892
Clin Cancer Res. 2018 Aug 1;24(15):3539-3549
pubmed: 29691297
JCO Precis Oncol. 2017 Jul;2017:
pubmed: 28890946
Cancer Discov. 2018 Jun;8(6):714-729
pubmed: 29650534
Clin Cancer Res. 2020 Jan 1;26(1):242-255
pubmed: 31585938
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nature. 2019 Jul;571(7766):576-579
pubmed: 31292550
Ann Oncol. 2020 Dec;31(12):1725-1733
pubmed: 33007380
Clin Cancer Res. 2014 May 1;20(9):2249-56
pubmed: 24789032
Nat Commun. 2021 Jun 18;12(1):3770
pubmed: 34145282
JCO Precis Oncol. 2017;2017:
pubmed: 30211344
J Clin Oncol. 2019 Jun 1;37(16):1370-1379
pubmed: 30892989
Mol Cancer Ther. 2017 Aug;16(8):1623-1633
pubmed: 28500237
Nature. 2017 Aug 10;548(7666):234-238
pubmed: 28783719
J Mol Diagn. 2015 May;17(3):251-64
pubmed: 25801821