Genomic and Transcriptomic Analysis of Neuroendocrine Transformation in ALK-Rearranged Lung Adenocarcinoma After Treatments With Sequential ALK Inhibitors: A Brief Report

Abstract

Introduction: Neuroendocrine (NE) transformation has been reported in patients with ALK-rearranged NSCLC after ALK inhibition, but unlike EGFR-mutant NSCLC, the exact mechanism of NE transformation in ALK-rearranged NSCLC is poorly studied. Methods: We collected the matched pre- and post-transformation samples from a patient with ALK-rearranged lung adenocarcinoma (LUAD) and performed targeted panel sequencing, whole exome sequencing, and bulk RNA sequencing. Results: Multiple mutations were shared between the pretransformation and post-transformation samples. Neither RB1 nor TP53 mutation was detected, but CDKN2A deletion and CDK4 amplification were found instead. Mismatch repair-associated mutational signature was significantly enriched after transformation. Genes associated with Notch signaling and PI3K/AKT pathway were significantly up-regulated, whereas genes related to lymphocyte activation and NF-kB signaling were down-regulated. Signatures relating to homologous recombination, mismatch repair, and Notch signaling pathways were enriched, which were further validated in The Cancer Genome Atlas cohorts. Macrophages M2 were found to have prominently higher abundance in the tumor immune microenvironment after NE transformation. Conclusions: The mechanism of NE transformation in ALK-rearranged LUAD may be different from that in EGFR-mutant LUAD.

Keywords

• ALK-SYNE1 fusion
• Neuroendocrine transformation
• CDK4
• Notch
• M2 macrophage