Histological and Molecular Plasticity of ALK-positive Non-Small-Cell Lung Cancer under Targeted Therapy - a Case Report

Abstract

With medical progress in cancer therapy, tyrosine kinase inhibitors (TKIs) became a standard of care for many cancer types. But the broad range of possible targeted therapies was accompanied by a plethora of potential resistance mechanisms, of which many have still to be identified. Here, we present the case of a patient with an EML4-ALK translocated non-small-cell lung cancer treated with four different TKIs. His tumor developed not only a well-known ALK-TKI resistance mutation, but also underwent a histological transformation from adenocarcinoma to squamous cell carcinoma. To confirm a shared monoclonal origin of the phenotypically different tumors, a phylogenetic reconstruction was conducted: this revealed a cluster of mutations including NFE2L2, KMT2D and MLH1 which are possible triggering events for the transformation.