Bellini and colleagues demonstrate the importance of next-generation sequencing to uncover subclonal anaplastic lymphoma kinase (ALK) mutations in neuroblastoma.
Here, we report similar basal patterns of ALK phosphorylation between the neuroblastoma IMR-32 cell line, which expresses only the wild-type receptor (ALK(WT)), and the SH-SY5Y cell line, which exhibits a heterozygous ALKF1174L mutation and expresses both ALK(WT) and ALK(F1174L) receptors.
Over the last few years, studies have demonstrated the occurrence of autophagy in different Anaplastic Lymphoma Kinase (ALK)-associated cancers, notably ALK-positive anaplastic large cell lymphoma (ALCL), non-small cell lung carcinoma (NSCLC), Neuroblastoma (NB), and Rhabdomyosarcoma (RMS).
We have analyzed tyrosine kinase domain mutations and amplification/expression of the ALK gene and focused on clinical features of neuroblastoma cases with ALK aberrations.
A variety of human malignancies have anaplastic lymphoma kinase (ALK) translocations, amplifications, or oncogenic mutations, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, non-small cell lung cancer, and neuroblastoma.
Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases.
This small-molecule inhibitor was shown to efficiently inhibit the growth of patient-derived and established neuroblastoma xenograft models expressing mutated ALK.
The currently recognized 2016 World Health Organization classification for RCC subtypes is briefly discussed, including new diagnostic entities (clear cell papillary RCC, hereditary leiomyomatosis and RCC-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, and acquired cystic disease-associated RCC) and areas of evolving RCC classification, such as transcription elongation factor B subunit 1 (TCEB1)-mutated RCC/RCC with angioleiomyoma-like stroma/RCC with leiomyomatous stroma, RCC associated with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement, thyroidlike follicular RCC, and RCC in neuroblastoma survivors.
Potential molecular targets in neuroblastoma include ALK mutations, p16 deletion and CDK2A mutations; however, targeted therapeutics have not been developed for these factors.
Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALK(F1174L) mutation at the time of diagnosis.
Alterations in anaplastic lymphoma kinase (<i>ALK</i>) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented.
Universal mass screening for neuroblastoma is not indicated but targeted screening of infants at risk of hereditary neuroblastoma with germline ALK or PHOX2B mutations is appropriate.
A 77-gene ALK signature was established and successfully validated in primary neuroblastoma samples, in a neuroblastoma cell line with ALK(F1174L) and ALK(R1275Q) regulable overexpression constructs and in other ALKomas.
This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases.
Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1.
Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes.
These data can be used to perform differential expression analysis based on a genetic aberration or phenotype in neuroblastoma (e.g., MYCN amplification status, ALK mutation status, chromosome arm 1p, 11q and/or 17q status, sensitivity to pharmacologic perturbation).
Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging.
An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.