Reference Detail

Ref Type

Journal Article

PMID

(35689207)

Authors

Berlak M, Tucker E, Dorel M, Winkler A, McGearey A, Rodriguez-Fos E, da Costa BM, Barker K, Fyle E, Calton E, Eising S, Ober K, Hughes D, Koutroumanidou E, Carter P, Stankunaite R, Proszek P, Jain N, Rosswog C, Dorado-Garcia H, Molenaar JJ, Hubank M, Barone G, Anderson J, Lang P, Deubzer HE, Künkele A, Fischer M, Eggert A, Kloft C, Henssen AG, Boettcher M, Hertwig F, Blüthgen N, Chesler L, Schulte JH

Title

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer	21	1	2022 06 10	126	Mol Cancer

URL

Abstract Text

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 NRASQ61K 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.Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK F1174L NRAS Q61K	neuroblastoma	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of NRAS Q61K in a neuroblastoma cell line harboring ALK F1174L conferred resistance to Lorbrena (lorlatinib) in culture (PMID: 35689207).	35689207
ALK F1174L NRAS Q61K	neuroblastoma	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of NRAS Q61K in a neuroblastoma cell line harboring ALK F1174L conferred resistance to Zykadia (ceritinib) in culture (PMID: 35689207).	35689207