TY - JOUR
T1 - Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells
AU - Berlak, Mareike
AU - Tucker, Elizabeth
AU - Dorel, Mathurin
AU - Winkler, Annika
AU - McGearey, Aleixandria
AU - Rodriguez-Fos, Elias
AU - da Costa, Barbara Martins
AU - Barker, Karen
AU - Fyle, Elicia
AU - Calton, Elizabeth
AU - Eising, Selma
AU - Ober, Kim
AU - Hughes, Deborah
AU - Koutroumanidou, Eleni
AU - Carter, Paul
AU - Stankunaite, Reda
AU - Proszek, Paula
AU - Jain, Neha
AU - Rosswog, Carolina
AU - Dorado-Garcia, Heathcliff
AU - Molenaar, Jan Jasper
AU - Hubank, Mike
AU - Barone, Giuseppe
AU - Anderson, John
AU - Lang, Peter
AU - Deubzer, Hedwig Elisabeth
AU - Künkele, Annette
AU - Fischer, Matthias
AU - Eggert, Angelika
AU - Kloft, Charlotte
AU - Henssen, Anton George
AU - Boettcher, Michael
AU - Hertwig, Falk
AU - Blüthgen, Nils
AU - Chesler, Louis
AU - Schulte, Johannes Hubertus
N1 - © 2022. The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Anaplastic Lymphoma Kinase/genetics
KW - Cell Line, Tumor
KW - Child
KW - Humans
KW - Mutation
KW - Neuroblastoma/drug therapy
KW - Precision Medicine
KW - Protein Kinase Inhibitors/pharmacology
KW - Signal Transduction
UR - https://www.mendeley.com/catalogue/9eee1370-eeca-39a6-8e55-ae5453938a8f/
U2 - 10.1186/s12943-022-01583-z
DO - 10.1186/s12943-022-01583-z
M3 - Article
C2 - 35689207
SN - 1476-4598
VL - 21
SP - 126
JO - Molecular cancer
JF - Molecular cancer
IS - 1
ER -