Distinct asciminib sensitivity profiles between BCR::ABL1 p190 and p210 isoforms

Abstract BCR::ABL1 is the oncogenic driver of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia (ALL), with BCR::ABL1 p210 and p190 being the predominant isoforms. Asciminib, an inhibitor that specifically targets the ABL myristate pocket (STAMP), has demonstrated efficacy in both pre-clinical and clinical studies against p210-driven CML, including cases where resistance mediated by ATP-pocket mutations has developed during prior tyrosine kinase inhibitor (TKI) therapy. The resistant mutation profile of asciminib is currently considered largely distinct from that of ATP-competitive TKIs. In our study, we demonstrate that several ATP-pocket mutations, including the V299L, F311I, T315I, and F317C/L, confer high levels of resistance to asciminib in the p190 isoform (> 1000-fold increase in LD 50 asciminib values compared to non-mutated BCR::ABL1 p190), but remain sensitive when occurring in the p210 isoform. The T315A was the only tested mutation in BCR::ABL1 p190 sensitive to asciminib. Furthermore, cells expressing BCR::ABL1 p190 mutations exhibited decreased kinase inhibition following STAMP treatment, indicative of an active kinase. Analogous results were obtained for MK-4208 (formerly known as TERN-701), a clinically active investigational STAMP compound. In the BCR::ABL1 p190 setting, this work reveals an overlapping resistance profile between STAMP compounds and TKIs, with important considerations for STAMP-based therapy. It challenges two key assumptions: that asciminib dose escalation can overcome resistant ATP-pocket mutations and that targeted therapy sensitivity profiles are equivalent between the p190 and p210 isoforms.