Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia

Abstract

Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CML) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CML, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. ( Chronic myeloid leukemia (CML) results from the balanced translocation of c-ABL from chromosome 9 and BCR on chromosome 22 leading to the formation of BCR-ABL1 chimeric oncoprotein, the product of the BCR-ABL1 hybrid gene, with constitutive tyrosine kinase activity (1, 2). Deregulated BCR-ABL1 activity results in enhanced cellular proliferation, and resistance to apoptosis and oncogenesis (3, 4). CML naturally progresses through distinct phases from early chronic phase to an intermediate accelerated phase followed by a terminal blast phase. Imatinib, the first tyrosine kinase inhibitor (TKI) approved for the treatment of CML (5), is a phenylaminopyridimine, which principally targets the tyrosine kinase activity of BCR-ABL1, exclusively binding to BCR-ABL1 in the inactive conformation in addition to inhibitory effects on KIT, ARG, and PDGFR kinases (6). The recent update of the phase III randomized IRIS study (International Randomized Study of Interferon-α plus Ara-C versus STI571) prospectively comparing imatinib with interferon-α and cytarabine in previously untreated patients in first chronic phase showed the best observed rate for a complete cytogenetic response [CCyR; or an undetectable number of Philadelphia chromosome positive (Ph+) chromosomes by conventional metaphase analysis] on imatinib of 82% at 6 years (7), with a declining annual rate of progression as the molecular response improved with time.

Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance

“…FGFR3 or RAS mutations are mutually exclusive in UC, 46 and as mutant RAS activates many of the same effector pathways, it may circumvent the requirement for FGFR Acquired resistance to FGFRi arising from a gatekeeper mutation in FGFR3 Acquired resistance to TKIs can arise through multiple mechanisms. [33][34][35] KMS-11R cells with acquired resistance to AZ8010 were cross-resistant to AZD4547 and PD173074, and sequencing revealed a point mutation at the gatekeeper residue (FGFR3 V555M ). Gatekeeper mutations typically inhibit drug binding in the ATP-binding site and also increase the activity of the kinase domain by facilitating assembly of an enzymatically active kinase conformation.…”

“…33,34 As new FGFRi enter clinical trials, it is timely to anticipate possible mechanisms of acquired resistance. As clinically relevant resistance mechanisms can be discovered by modelling in cell culture, 34,35 we generated AZ8010-resistant derivatives of the KMS-11 MM cell line (KMS-11R cells). KMS-11R cells grew at the same rate as parental KMS-11 cells (Supplementary Figure 6A), were B100-fold resistant to AZ8010 in proliferation assays ( Figure 5a) and were also resistant in cell death assays (Figure 5b).…”

Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7

“…Additional confirmations, many very recently, of the up-regulation of the receptor in cancer tissue have been obtained for pancreatic [43], lung [44], skin [45][46][47], brain [48,49], renal [38], prostate [50], thyroid [51], bone [52] and both ALL and AML [53,54].…”

“…The benefits are specific targeting, lower doses needed to target the tumour, and no unwanted side effects from off-target binding. That the target is highly conserved across species indicates that mutational drift in the target, as a result of therapeutic intervention, as is the case with easily mutable targets such as BCR-ABL, c-KIT and PDGFRA tyrosine kinases [53,54], is less likely to occur.…”

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

“…8A). However, a reduced expression or activity of the OCT1 transporter which mediates imatinib influx [50] could also explain this result.…”