Asciminib with Ponatinib Lowers Resistance in Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKI) have shown efficacy in chronic myeloid leukemia (CML), but point mutation–mediated resistance often develops, and therapeutic options in some cases are limited. Eide, Zabriskie, and colleagues found that combining the allosteric BCR–ABL1 inhibitor asciminib with the ATP-site TKI ponatinib may restore efficacy in cases in which multiple point mutations in the same BCR–ABL1 allele (compound mutations) have led to resistance. Ex vivo experiments using primary CML cells showed that asciminib treatment resulted in a reduction in BCR–ABL1 signaling; it also inhibited colony formation, an effect not seen in healthy control cells. In mouse hematopoietic cell lines, asciminib had varying effectiveness in lines bearing different BCR–ABL1 mutations previously found to be associated with resistance to approved ATP-site TKIs. In contrast, combination treatment with asciminib and ponatinib prevented the emergence of resistant mutants. Analysis of serial samples from six patients who ultimately discontinued asciminib revealed that mutations at position 359, which lies within the kinase domain, were increased with asciminib treatment and associated with resistance. In primary CML cells, asciminib appeared to potentiate the effects of ponatinib and nilotinib (another ATP-site TKI), reducing BCR–ABL1 signaling and clonogenicity. Notably, combination treatment with asciminib and ponatinib at clinically relevant concentrations was effective in cells with multiple BCR–ABL1 mutations, whereas treatment with either agent alone failed. In mice injected with mouse hematopoietic cells expressing BCR–ABL1 harboring compound mutations, combination treatment with asciminib and ponatinib produced a modest but statistically significant improvement in survival and decreased tumor burden compared with either treatment alone. Hinting at a mechanism, molecular-dynamics simulations indicated that transient binding of ponatinib to a resistance-associated compound BCR–ABL1 mutant increased the favorability of asciminib binding, which further stabilized the ponatinib-bound state. This work suggests that combination treatment with asciminib and ponatinib may be of use in patients with multiple resistance-associated mutations in BCR–ABL1, including compound mutations, and may even reduce the likelihood of their emergence.

Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell 2019 Sep 19 [Epub ahead of print].

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