Heterogeneous distribution of alectinib in neuroblastoma xenografts revealed by matrix‐assisted laser desorption ionization mass spectrometry imaging: a pilot study

Abstract

BACKGROUND AND PURPOSEThe penetration of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in neuroblastomas and the relationship between alectinib and ALK expression are unknown. The aim of this study was to perform a quantitative investigation of the inter-and intratumoural distribution of alectinib in different neuroblastoma xenograft models using matrix-assisted laser desorption ionization MS imaging (MALDI-MSI). EXPERIMENTAL APPROACHThe distribution of alectinib in NB1 (ALK amplification) and SK-N-FI (ALK wild-type) xenograft tissues was analysed using MALDI-MSI. The abundance of alectinib in tumours and intra-tumoural areas was quantified using ion signal intensities from MALDI-MSI after normalization by correlation with LC-MS/MS. KEY RESULTSThe distribution of alectinib was heterogeneous in neuroblastomas. The penetration of alectinib was not significantly different between ALK amplification and ALK wide-type tissues using both LC-MS/MS concentrations and MSI intensities. Normalization with an internal standard increased the quantitative property of MSI by adjusting for the ion suppression effect. The distribution of alectinib in different intra-tumoural areas can alternatively be quantified from MS images by correlation with LC-MS/MS. CONCLUSION AND IMPLICATIONSThe penetration of alectinib into tumour tissues may not be homogenous or influenced by ALK expression in the early period after single-dose administration. MALDI-MSI may prove to be a valuable pharmaceutical method for elucidating the mechanism of action of drugs by clarifying their microscopic distribution in heterogeneous tissues. AbbreviationsALK, anaplastic lymphoma kinase; FA, formic acid; ITO, indium titanium oxide; MALDI-MSI, matrix-assisted laser desorption ionization MS imaging; ROIs, regions of interest; RTKIs, RTK inhibitors; RTKs, receptor TKs; α-CHCA, α-cyano-4-hydroxycinnamic acid

Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report

“…However, there are few studies investigating the effect of ALK VAF in NSCLC and the majority of existing studies are based on circulating tumor DNA (ctDNA), which may be not appropriate to compare with tissue biopsies. Although higher ALK VAF may suggest a better response of ALK-TKI treatment in theory, interestingly, correlation between ALK expression levels and alectinib penetration in the tumor was not observed early after the administration of single dose in neuroblastoma xenografts ( 33 ). Further investigation on revealing the correlation between VAF and high CNS penetrance of alectinib may benefit the better clinical application of alectinib at an individualized level ( 34 ).…”

The Space Dimension at the Micro Level: Mass Spectrometry Imaging of Drugs in Tissues

“…Normalization has been done using the total ion current (Deininger et al, 2011), the signal from matrix cluster ions (Takai et al, 2012) or a reference peak from a molecule evenly present in the tissue (Hankin & Murphy, 2010) or added to the matrix (Takai, Tanaka, & Saji, 2014). Adding an internal standard to the matrix has given the best results for drug local concentrations in tissue (Ryu et al, 2018; Tang et al, 2019). Stable isotope‐labeled analytes of the molecule of interest have proved the best choice as internal standard because of their identical ionization and extraction characteristics.…”

“…Creating molecular images with mass spectrometry imaging (MSI) opens the way for the pharmacologist to characterize the distribution of a drug accurately inside the tissue and its substructures. This approach has been increasingly used for preclinical studies, for example, to characterize the distribution of anticancer drugs inside tumor tissue (Giordano et al, 2016; Végvári et al, 2016; Ryu et al, 2018), the central nervous system (Ntshangase et al, 2019) or normal organs (Tang et al, 2019).…”

Precision pharmacology: Mass spectrometry imaging and pharmacokinetic drug resistance

“…In this experiment D8-alectinib (i.e. deuterated alectinib) was added to the matrix in order to correct possible ion suppression from endogenous tissue components or the matrix and, therefore, to verify the heterogeneity of alectinib distribution (Ryu et al, 2018). In another study using a colorectal xenograft model, composite images showed that some areas of the tumour with higher VEGFR2 expression had higher sunitinib concentrations.…”