Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : firstname.lastname@example.org
|Ref Type||Journal Article|
|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.|
|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.|
|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||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|
|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|