Sustained Response to Entrectinib in an Infant With a Germline ALKAL2 Variant and Refractory Metastatic Neuroblastoma With Chromosomal 2p Gain and Anaplastic Lymphoma Kinase and Tropomyosin Receptor Kinase Activation

Abstract

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A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

“…We conclude, therefore, that alternative TrkAIII mRNA splicing, leading to intracellular expression and activation of the TrkAIII oncoprotein, is likely to participate in PitNET pathogenesis and progression. TrkAIII may, therefore, represent a novel potential oncogenic target for clinically approved Trk inhibitors in refractory PitNETs [ 57 , 58 ].…”

Neuroblastoma Heterogeneity, Plasticity, and Emerging Therapies

“…Eventually, it became evident that different ALK hotspot mutations in neuroblastoma confer differential sensitivity toward different ALK inhibitors [ 87 – 89 ]. In selected cases, individualized preclinical evaluation of a newly described ALK or ALK ligand mutation has proven beneficial [ 84 , 90 ]. Secondary resistance toward ALK inhibitors is a frequent observation in NSCLC patients and is also seen in neuroblastoma patients, and sometimes the switch to an alternative ALK inhibitor becomes necessary [ 91 ].…”

“…In general, ALK inhibitors cause low toxicity, allowing their use even under circumstances when chemotherapy cannot be tolerated [ 90 ]. A number of responders have remained on ALK inhibitor treatment well beyond 1 year [ 84 , 86 , 88 , 90 , 92 ].…”

“…ALK, the second most common driver in neuroblastoma after MYCN, is a receptor tyrosine kinase which in the neuroblastoma context first attracted attention in conjunction with the rare hereditary neuroblastomas [ 15 ]. The oncogenic mechanism in neuroblastoma operates by activation of RAS-MAPK-ERK and other downstream pathways, and can be initiated by activating mutations of ALK , ALK amplifications, or, possibly, changes to the ALK ligands ALKAL1 and ALKAL2 [ 82 – 84 ]. The ALK gene is situated in proximity to MYCN and ALKAL2 on chromosome 2p and it has been argued that co-amplification of these three explains the inferior outcome in neuroblastoma patients with 2p gain [ 85 ].…”

Çocukluk Çağı Kanserlerinde NTRK Somatik Füzyonları ve Tümör Agnostik Tedavi

“…The child, who has reached the age of 4, is still on entrectinib and celecoxib treatment, and his general condition has been reported to be good. [25] Safety and Adverse Effect Profile Studies regardless of molecular structure and cancer type have mostly been conducted on first generation TRK inhibitors (larotrectinib and entrectinib) and have shown that these two agents have favorable toxic profiles. The treatment-emergent adverse effects are believed to be the result of the inhibition of normal TRK receptors, which are not a product of a mutant gene, that has serius affects on embryonic central nervous system development and neural activity.…”