Comprehensive resistance profiling of ABL1 variants against six kinase inhibitors for CML treatment

Variants of uncertain significance (VUSs) hinder the clinical application of genetic information particularly for precision medicine. A prime example is chronic myelogenous leukemia (CML); there are six clinically used tyrosine kinase inhibitors but selecting the most appropriate one for a given individual patient with ABL1 mutations is currently challenging. Here, we used prime editing to generate 92% (= 2,656/2,892) of all possible single nucleotide variants in the sequence encoding the ABL1 kinase domain, which encode 93% (= 1,855/1,998) of all possible corresponding single amino acid variants (SAAVs), and evaluated their effects on resistance to the six TKIs in clinical use (imatinib, nilotinib, bosutinib, dasatinib, ponatinib, and asciminib) in CML-relevant K562 cells. We identified 179 novel pairs of resistance-conferring SAAVs and the corresponding TKIs. Our comprehensive resistance map will help in drug selection for CML patients based on ABL1 mutations, facilitating precision medicine.