Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.
ALK
CRISPR screening
Ceritinib
Collateral sensitivity
Lorlatinib
NF1
NRAS
Neuroblastoma
Resistance
Trametinib
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
10 06 2022
10 06 2022
Historique:
received:
09
01
2022
accepted:
22
04
2022
entrez:
10
6
2022
pubmed:
11
6
2022
medline:
15
6
2022
Statut:
epublish
Résumé
Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRAS Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.
Sections du résumé
BACKGROUND
Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations.
METHODS
Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled.
RESULTS
Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRAS
CONCLUSIONS
Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.
Identifiants
pubmed: 35689207
doi: 10.1186/s12943-022-01583-z
pii: 10.1186/s12943-022-01583-z
pmc: PMC9185889
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
126Informations de copyright
© 2022. The Author(s).
Références
Am J Surg Pathol. 1997 Dec;21(12):1420-32
pubmed: 9414185
PLoS Comput Biol. 2021 Nov 4;17(11):e1009515
pubmed: 34735429
Cancer Discov. 2014 May;4(5):606-19
pubmed: 24535670
Clin Cancer Res. 2009 Dec 15;15(24):7471-7478
pubmed: 20008847
Mol Syst Biol. 2011 May 24;7:489
pubmed: 21613978
Sci Signal. 2015 Apr 28;8(374):ra40
pubmed: 25921289
Nat Biotechnol. 2018 Feb;36(2):170-178
pubmed: 29334369
Lancet Oncol. 2013 May;14(6):472-80
pubmed: 23598171
Mol Cancer Ther. 2012 Apr;11(4):909-20
pubmed: 22389471
Cell. 1986 Jan 17;44(1):167-76
pubmed: 3510078
J Clin Oncol. 2014 Sep 1;32(25):2727-34
pubmed: 25071110
N Engl J Med. 2020 Nov 19;383(21):2018-2029
pubmed: 33207094
Bioinformatics. 2008 Mar 15;24(6):840-7
pubmed: 18218655
Cancer Res. 2008 Aug 1;68(15):6145-53
pubmed: 18676837
Nature. 2008 Oct 16;455(7215):930-5
pubmed: 18724359
J Clin Oncol. 2009 Jan 10;27(2):289-97
pubmed: 19047291
Cold Spring Harb Mol Case Stud. 2021 Aug 2;7(4):
pubmed: 34210658
Nat Clin Pract Oncol. 2006 May;3(5):269-80
pubmed: 16683005
Mol Oncol. 2014 Sep 12;8(6):1067-83
pubmed: 24910388
Mod Pathol. 2001 Jun;14(6):569-76
pubmed: 11406658
Clin Cancer Res. 2015 Jul 15;21(14):3327-39
pubmed: 25805801
Nature. 1992 Apr 23;356(6371):713-5
pubmed: 1570015
Sci Transl Med. 2012 Jul 4;4(141):141ra91
pubmed: 22764207
Nature. 2008 Oct 16;455(7215):975-8
pubmed: 18923525
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
Nature. 2008 Oct 16;455(7215):971-4
pubmed: 18923524
Nat Commun. 2019 Nov 28;10(1):5428
pubmed: 31780656
Genome Biol. 2015 Dec 16;16:281
pubmed: 26673418
Mol Syst Biol. 2013;9:673
pubmed: 23752269
Nat Commun. 2018 Dec 21;9(1):5416
pubmed: 30575746
Klin Padiatr. 2017 May;229(3):147-167
pubmed: 28561228
Lancet. 2020 Mar 28;395(10229):1078-1088
pubmed: 32222192
Biochem J. 2008 Dec 1;416(2):153-9
pubmed: 18990089
Lancet Oncol. 2009 Oct;10(10):992-1000
pubmed: 19796751
J Clin Oncol. 2021 Oct 20;39(30):3377-3390
pubmed: 34115544
Nature. 2008 Oct 16;455(7215):967-70
pubmed: 18923523
Nat Genet. 2015 Aug;47(8):864-71
pubmed: 26121087
Pediatr Blood Cancer. 2011 Apr;56(4):578-83
pubmed: 21298742
Nat Chem Biol. 2017 Dec;13(12):1222-1231
pubmed: 28991240
J Am Med Inform Assoc. 2016 Jul;23(4):721-30
pubmed: 27026619
Bioinformatics. 2018 Dec 1;34(23):4079-4086
pubmed: 29931053
Br J Cancer. 2010 May 25;102(11):1555-77
pubmed: 20502460
Nat Rev Cancer. 2013 Oct;13(10):685-700
pubmed: 24060861
Cancer Biol Ther. 2018;19(10):871-874
pubmed: 30036146
Clin Cancer Res. 2021 Jul 1;27(13):3543-3548
pubmed: 33568345
Adv Cancer Res. 1963;7:235-50
pubmed: 14153767
Nat Rev Cancer. 2003 Mar;3(3):203-16
pubmed: 12612655
Cell. 2017 Jun 29;170(1):17-33
pubmed: 28666118
Nature. 2007 Aug 2;448(7153):561-6
pubmed: 17625570
PLoS Genet. 2016 Dec 20;12(12):e1006501
pubmed: 27997549
Cell. 2010 Jul 23;142(2):218-29
pubmed: 20655465
Carcinogenesis. 2005 Dec;26(12):2105-15
pubmed: 16051641
Cancer Res. 2018 Dec 15;78(24):6866-6880
pubmed: 30322862
Science. 2018 Dec 7;362(6419):1165-1170
pubmed: 30523111
Nature. 1985 Feb 21-27;313(6004):700-3
pubmed: 3919305
Oncogene. 2016 Jul 14;35(28):3681-91
pubmed: 26616860
Clin Cancer Res. 2020 Feb 1;26(3):608-622
pubmed: 31591187
Cancers (Basel). 2021 Feb 09;13(4):
pubmed: 33572278
Cancer Discov. 2013 Mar;3(3):350-62
pubmed: 23288408
Nat Genet. 1996 Feb;12(2):144-8
pubmed: 8563751
Nature. 2019 Aug;572(7771):676-680
pubmed: 31391581
Clin Cancer Res. 2010 Sep 1;16(17):4353-62
pubmed: 20719933
N Engl J Med. 2010 Jun 10;362(23):2202-11
pubmed: 20558371
Lancet Oncol. 2021 Dec;22(12):1764-1776
pubmed: 34780709