Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

Abstract

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification.

Next-Generation Sequencing with Liquid Biopsies from Treatment-Naïve Non-Small Cell Lung Carcinoma Patients

“…So far, LB for lung cancer patients has been shown to be of strong interest during tumor progression, notably for tracking different mechanisms of resistance that can be targeted by different therapeutic agents [ 30 , 54 , 55 , 56 , 57 , 58 ]. Initially LB was orientated to targeted sequencing in EGFR , while looking for the T790M mutation in patients treated with first- or second-line tyrosine kinase inhibitors (TKIs) [ 20 , 21 , 37 ].…”

“…Initially LB was orientated to targeted sequencing in EGFR , while looking for the T790M mutation in patients treated with first- or second-line tyrosine kinase inhibitors (TKIs) [ 20 , 21 , 37 ]. However, the mechanisms of resistance at tumor progression can be complex and can involve different mutations, amplifications or fusions in different genes, which limits the interest of using a targeted sequencing approach for tracking these mechanisms [ 55 , 59 , 60 ]. This is particularly the case for patients receiving a third-generation EGFR TKIs who may present many different genetic alterations on tumor progression [ 20 , 21 ].…”

“…So, using targeted sequencing for one gene with a LB is limiting and this highlights the strong interest of using a NGS method. Similarly, resistance mechanisms, notably ALK mutations can be investigated with a LB on tumor progression in patients treated with ALK inhibitors [ 55 ]. The presence of ALK mutations can be associated with some specific targeted therapies [ 41 , 55 , 61 , 62 ].…”

“…Similarly, resistance mechanisms, notably ALK mutations can be investigated with a LB on tumor progression in patients treated with ALK inhibitors [ 55 ]. The presence of ALK mutations can be associated with some specific targeted therapies [ 41 , 55 , 61 , 62 ]. However, the sensitivity of NGS with a LB could be lower than that with a TB, notably for the detection of gene amplifications and fusions, which makes renewal of a TB of interest on tumor progression [ 63 ].…”

“…A LB at diagnosis in late stage lung cancer has been developed using mostly targeted sequencing, notably for the detection of EGFR mutations or ALK/ROS1 fusions [ 21 , 37 , 40 , 55 ]. However, as a tumor progresses, NGS with a LB at baseline allows many genomic alterations on different genes to be detected and holds many advantages in comparison to NGS with a TB.…”