These data demonstrate that ALK is a bona fide immunotherapeutic target and provide a rationale for clinical development of an ALK-ADC approach for neuroblastomas and other ALK-expressing childhood cancers such as rhabdomyosarcomas.
In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in <i>PTCH1</i> or gain-of-function mutations in <i>SMO</i>, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma.
We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient.
We identified novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF), and a novel PAX3-GLI2 fusion in a rhabdomyosarcoma.
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).
Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status.
Anaplastic lymphoma kinase may also have an oncogenic role in rhabdomyosarcomas and peripheral neuroblastic tumors, and they may possibly be treated with ALK inhibitors.
In vitro treatment with crizotinib inhibited ALK and MET proteins, as well as Insulin-like Growth Factor 1 Receptor (IGF1R), with a concomitant robust dephosphorylation of AKT and ERK, two downstream kinases involved in RMS cell proliferation and survival.
Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma.
We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort.
Quantitative assessment of ALK mRNA expression helps to improve risk stratification of RMS patients and identifies tumours with adverse biological characteristics and aggressive behaviour.
Expression of GLI1 with or without PTCH was detected in substantial subsets of embryonal RMS (ERMS) and US tumors but only rarely in alveolar RMS tumors.