Response and Resistance of ALK-mutated Neuroblastoma Cells to Ceritinib

Introduction:

Despite intensive therapy, more than 50% of patients with high-risk Neuroblastoma (NB) relapse, which mostly results in a fatal outcome. Activating mutations of the Anaplastic Lymphoma Kinase (ALK) are present in approx. 15% of high-risk NB. A pediatric phase I/II trial with the ALK inhibitor (ALKi) Ceritinib revealed a safe tolerable dose in children. Most patients with relapsed NB eventually relapsed during Ceritinib treatment due to ALKi resistance.

Methods:

We subjected tumor biopsies of two high-risk NB patients collected before ALKi therapy and after the time of relapse to targeted sequencing.

Results:

An acquired mutation inactivating NF1 was identified, suggesting that secondary genomic events activate RAS signaling. PDX were established before and after relapse for further analyses. We analyzed the transcriptional response to ALKi treatment in PDX cultures and in ALK-mutated NB cell lines and focused on the identification and functional evaluation of convergent targets. Our results provide a rationale for clinical trials that investigate those targets and Ceritinib in combinatorial treatments to tackle ALKi resistance mechanisms.