Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors

Abstract

Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1-dependent and BCR-ABL1-independent mechanisms continues to be an issue. BCR-ABL1-dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1-independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy.

Keywords: BCR-ABL1; Chronic myeloid leukemia (CML); Drug resistance; Mutation; Treatment-free remission (TFR); Tyrosine kinase inhibitor (TKI).

Figure 1

BCR-ABL1-dependent vs. independent resistance. (A) Native BCR-ABL1 signaling in the absence of TKI inhibition is necessary and sufficient for leukemogenesis in CML. (B) Kinase domain mutations in BCR-ABL1 can alter the binding of TKIs and lead to reconstitution of BCR-ABL1 signaling. (C) In the setting of effective BCR-ABL1 inhibition with TKIs, leukemia cells persist due to activation of alternative survival pathways.

Figure 2

Type I and Type II inhibitors. (A) Type II inhibitors stabilize the inactive conformation of BCR-ABL1 in which the activation loop is closed and the DFG is in an outward (“DFG out”) orientation. (B) Type I inhibitors are ATP-competitive, binding to BCR-ABL1 when the activation loop is in an open position conformation and the DFG motif is oriented toward the catalytic site (“DFG-in”). Courtesy of T. Clackson, PhD, Cambridge, MA.

Figure 3

Key residues influence BCR-ABL1-dependent resistance to TKIs. (A) Crystal structure of the ABL1 kinase domain in complex with imatinib. Twelve positions (in orange, T315 in red) account for most clinical BCR-ABL1 TKI resistance. The phosphate-binding (yellow) and activation loops (green) are indicated. (B) Superposition of imatinib and AP24534 (ponatinib) highlighting the effect of the Thr to Ile mutation. High-affinity binding of imatinib and other 2G TKIs to BCR-ABL1 requires a critical hydrogen bond with residue T315, which is eliminated upon the conversion of threonine to isoleucine. Unlike other clinically available TKIs, ponatinib does not form a hydrogen bond with T315 and has activity against the T315I mutant form of BCR-ABL1. Figure 3A: From Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 2014; 26(3); 430; with permission. Figure 3B: From O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16(5): 403; with permission.

Figure 4

Activity of TKIs against mutant isoforms of BCR-ABL1 in Ba/F3 cells. The relative increase in IC50 value over wild-type BCR-ABL1 is depicted for each TKI against single BCR-ABL1 mutants. Green indicates sensitive mutants, yellow indicates moderate resistance and yellow indicates marked resistance. In patients, TKI efficacy is dependent on other factors, such as oral and cellular bioavailability. From Eiring AM, Deininger MW. Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biol 2014;15(9):461; with permission.