Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Abstract

SUMMARY BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP-site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib’s effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.

Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells

“…42) Overexpression of Bcr-Abl is one critical key of inducing mutation and resistance and enhancing self-renewal of CML stem cells. 13,14) However, it has not been provided how to resolve the CML resistant barrier of increased Bcr-Abl expression effectively. Many studies indicated that emodin, a major component in rheum, showed multiple effects in cancer therapy, including tumor growth inhibition, apoptosis induction, toxicity sensitization and migration inhibition.…”

“…13) Besides, it seemed that Bcr-Abl overexpression enhanced self-renewal of CML stem cells. 14) In other cases, activation of prooncogenic signaling pathways and molecules, such as signal transducers and activators of transcription 5 (STAT5) and Src kinases, have been described as avoiding TKI treatment and contributing to CML resistance.…”

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

“…Despite encouraging preclinical and clinical data, several issues remain to be addressed in asciminib monotherapy: (1) emergence of resistance due to point mutations in myristoyl-binding site, (2) ineffectiveness towards compound mutant cells. Eide at al [158] described several mutations in the myristoyl-binding site accounting for asciminib-resistant phenotype, which was completely abrogated by addition of nilotinib or ponatinib. More importantly, the combination of asciminib and ponatinib effectively diminished the viability of compound mutant cells and prolonged the survival of leukemia-bearing mice, thus showing great promise for resistant and relapsed Ph+ patients [158].…”

“…Eide at al [158] described several mutations in the myristoyl-binding site accounting for asciminib-resistant phenotype, which was completely abrogated by addition of nilotinib or ponatinib. More importantly, the combination of asciminib and ponatinib effectively diminished the viability of compound mutant cells and prolonged the survival of leukemia-bearing mice, thus showing great promise for resistant and relapsed Ph+ patients [158]. Accordingly, many clinical trials are currently recruiting CML and Ph+ ALL patients to evaluate the efficacy of asciminib in combination with other TKIs (NCT03595917, NCT03578367, NCT02081378).…”

Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to

“…The combination use of ABL001 and ATP competitive Bcr-Abl inhibitors (such as nilotinib and ponatinib) was effective in overcoming resistance problems, due to mutations both at the ATP binding site or the ones observed near the allosteric myristoyl binding pocket [ 68 , 69 ]. ABL001 is currently in clinical trials for the treatment of CML and Ph+ ALL as a single agent and in combination with imatinib (NCT03106779 and NCT03578367, respectively).…”