Somatic genome variants caused by major structural variants, such as the t(9;22) chromosomal translocation producing the BCR ABL1 fusion gene, are major mechanisms underlying many forms of hematopoietic malignancies. The increased tyrosine kinase activity of the BCR-ABL1 protein (encoded by the chimeric BCR-ABL1 or “Philadelphia [Ph] chromosome”) is the driving oncogenic event in the majority of patients with CML and in a subset of patients with poor-prognosis ALL. This realization resulted in the development of specific TKIs. The treatment of CML was revolutionized with the introduction of the first TKI STI-571 (imatinib), a small molecular-weight drug that binds to the kinase domain of ABL1, thereby leading to inhibition of tyrosine phosphorylation of proteins involved in downstream signal transduction. In the landmark phase III International Randomized Study of Interferon alpha (IFN-α) and STI-571 (IRIS) trial, imatinib monotherapy was established as the standard-of-care for CML patients, which led to a paradigm shift in cancer treatment (i.e., a more targeted therapy instead of the nonspecific inhibition of rapidly dividing cells).

Although long-term outcome of IRIS participants was excellent in the imatinib arm (with 83.3% survival at 10 years and infrequent serious side effects), up to 17% of patients had been identified to have developed resistance to imatinib within 5 years of therapy. Both, BCR-ABL1 kinase–dependent (i.e., mutations in or near to the imatinib binding site of the target kinase domain of ABL1, found in 60% of the patients who relapsed after achieving an initial response) and BCR-ABL1–independent drug resistance mechanisms were subsequently identified. The latter include reactivation of downstream signaling pathways (e.g., Janus kinase/signal transducer and activator of transcription proteins [JAK/STAT], mitogen-activated protein kinase [MAPK], or phosphatidylinositol 3-kinase [PI3K]) despite effective BCR-ABL1 inhibition; mutations in epigenetic regulators such as DNA methyltransferase 3 alpha (DNMT3A) and isocitrate dehydrogenase 1 (IDH1); or microenvironmental factors such as cytokines that influence, for example, STAT3 phosphorylation independent of BCR-ABL1 kinase activity. BCR-ABL1 kinase–independent resistance mechanisms predominate in primary resistant CML clones.[1] Sequence variants governing BCR-ABL1 kinase–dependent drug resistance are localized either around the phosphate binding loop (e.g., variants M244V, G250E, Q252H, Y253F, E255V), the SH2 contact and C-lobe (e.g., variants M351T, F359V), the activation loop (e.g., variant H396P, H396R), or the gatekeeper residue (variants T315I and F317L) of the imatinib binding site. [1]  The identification of these variants led to the design of second- and third-generation ABL1 TKIs. Of these, currently four are FDA approved for the therapy of CML, namely nilotinib (binding to the same pocket as imatinib but with higher affinity; strong resistance: T315I), dasatinib (binds to the ATP-binding site with stronger activity against the ABL1 kinase compared with imatinib and dasatinib; strong resistance: T315I), bosutinib (similar binding site as dasatinib but lower potency; strong resistance: T315I, V299L), and ponatinib (high-affinity binding to ABL1 and efficacy also against T315I; compound mutations affecting E255V and T315I do result in drug resistance) [1]  (see also the website Clinical Interpretation of Variants in Cancer [CIViC]). The relatively common T315I or “gatekeeper” variant confers resistance to imatinib, nilotinib, dasatinib, and bosutinib; therefore the third-generation TKI ponatinib was designed. Ponatinib was successfully tested in clinical trials, and its use was first approved by the FDA in 2012 for patients with CML resistant to other TKIs. However, ponatinib was temporarily suspended in 2013 due to serious vascular adverse events (VAEs; i.e., arterial and venous thromboembolic events, arterial hypertension), and VAEs are now recognized as also limiting the use of second-generation TKIs. Moreover, the strong selective pressure of ponatinib has led to the emergence of TKI resistance due to so-called compound mutations in ABL1. Compound mutations are multiple point variants occurring in the same BCR-ABL1 allele, and this drug resistance mechanism is different to the emergence of multiple clones with different mutations. Computed modeling and in vitro proliferation studies were used to analyze the impact of compound mutations in BCR-ABL1 on TKI resistance and showed, for instance, that the compound mutation Y253H/E255V induced a shift in the P-loop of the ABL1 kinase, obstructing the ponatinib binding site, resulting in resistance to ponatinib. [2] Moreover, it was found that additional acquisition of an E255V variant in T315I-positive CML confers also resistance to ponatinib.

To avoid off-target toxicities of ponatenib and to retain the ability to target the T315I variant, the allosteric inhibitor asciminib (ABL001), which binds to the myristoylation pocket of BCR-ABL1, was designed. Asciminib showed promising results in a phase I clinical trial in heavily pretreated CML patients (NCT02081378); that its, a major molecular response (MMR; which is a BCR-ABL1 PCR level of 0.01% on the Internationale Scale [IS]) was achieved in 48% of patients at 12 months of therapy. [1] However, like for ATP-binding site TKIs, mutations at the binding site of asciminib can also cause resistance to this drug, and a combination of asciminib with an ATP binding site TKI may overcome the emergence of resistant CML clones because these drugs bind at different sites of BCR-ABL1 and have therefore different drug resistance mechanisms.

As second- and third-generation TKIs have a risk for VAEs, especially in older patients with preexisting vascular disease, TKI selection based on cardiovascular risk factors and mutational BCR-ABL1 status is of utmost importance to guide CML therapy. Upfront and repeated monitoring of the mutational status of patients with BCR ABL1–positive leukemias can help to select appropriate TKIs and tailor TKI treatment. Recent treatment trials also focus on combining TKIs with other drugs such as IFN-α (which can augment immune reaction against TKI-resistant residual CML clones; NCT01933906, NCT02001818) or with drugs that target signaling pathways downstream of the BCR-ABL1 kinase (e.g., the JAK inhibitor ruxolitinib; NCT01702064, NCT03610971) to overcome ABL1 kinase domain mutation–independent resistance mechanisms in order to promote deep molecular responses and to allow discontinuation of TKI therapy. [1]

References

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[1] Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1 targeted therapies. Cancer Cell. 2020;37(4):530–542.

[2] Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR–ABL1 compound mutations combining key domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26:428–442.

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