Berlak, Mareike ORCID: 0000-0003-4437-3477, Tucker, Elizabeth ORCID: 0000-0003-3716-6605, Dorel, Mathurin, Winkler, Annika, McGearey, Aleixandria, Rodriguez-Fos, Elias ORCID: 0000-0002-2555-0178, da Costa, Barbara Martins, Barker, Karen, Fyle, Elicia, Calton, Elizabeth, Eising, Selma, Ober, Kim, Hughes, Deborah, Koutroumanidou, Eleni, Carter, Paul, Stankunaite, Reda, Proszek, Paula ORCID: 0000-0002-0780-6790, Jain, Neha ORCID: 0000-0002-8499-3366, Rosswog, Carolina, Dorado-Garcia, Heathcliff, Molenaar, Jan Jasper, Hubank, Mike, Barone, Giuseppe, Anderson, John, Lang, Peter, Deubzer, Hedwig Elisabeth, Kuenkele, Annette, Fischer, Matthias, Eggert, Angelika ORCID: 0000-0003-3476-8184, Kloft, Charlotte, Henssen, Anton George, Boettcher, Michael, Hertwig, Falk, Bluthgen, Nils, Chesler, Louis and Schulte, Johannes Hubertus ORCID: 0000-0003-0671-1201 (2022). Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells. Mol. Cancer, 21 (1). LONDON: BMC. ISSN 1476-4598

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Abstract

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(Q61K) mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. Conclusions Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Berlak, MareikeUNSPECIFIEDorcid.org/0000-0003-4437-3477UNSPECIFIED
Tucker, ElizabethUNSPECIFIEDorcid.org/0000-0003-3716-6605UNSPECIFIED
Dorel, MathurinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winkler, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGearey, AleixandriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez-Fos, EliasUNSPECIFIEDorcid.org/0000-0002-2555-0178UNSPECIFIED
da Costa, Barbara MartinsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barker, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fyle, EliciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calton, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eising, SelmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ober, KimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hughes, DeborahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koutroumanidou, EleniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stankunaite, RedaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Proszek, PaulaUNSPECIFIEDorcid.org/0000-0002-0780-6790UNSPECIFIED
Jain, NehaUNSPECIFIEDorcid.org/0000-0002-8499-3366UNSPECIFIED
Rosswog, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorado-Garcia, HeathcliffUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molenaar, Jan JasperUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hubank, MikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barone, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderson, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deubzer, Hedwig ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuenkele, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDorcid.org/0000-0003-3476-8184UNSPECIFIED
Kloft, CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henssen, Anton GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boettcher, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertwig, FalkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bluthgen, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chesler, LouisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes HubertusUNSPECIFIEDorcid.org/0000-0003-0671-1201UNSPECIFIED
URN: urn:nbn:de:hbz:38-695063
DOI: 10.1186/s12943-022-01583-z
Journal or Publication Title: Mol. Cancer
Volume: 21
Number: 1
Date: 2022
Publisher: BMC
Place of Publication: LONDON
ISSN: 1476-4598
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RAS PROTEINS; ACTIVATING MUTATIONS; TARGETED THERAPY; KINASE; NF1; RECEPTOR; GENE; CLASSIFICATION; IDENTIFICATION; CRIZOTINIBMultiple languages
Biochemistry & Molecular Biology; OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69506

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