Overcoming Resistance to Tyrosine Kinase Inhibitors in CML

Chronic myeloid leukemia (CML), a form of slowly progressing blood and bone marrow disease, develops from the neoplastic transformation of hematopoietic stem cells. Transformed hematopoietic stem cells give rise to abnormal white blood cells, also known as leukemia cells. Excessive production of leukemia cells in the body reduce the number of  healthy white blood cells, red blood cells, and platelets in blood and bone marrow resulting our body susceptible to any sort of infection, anemia, or easy bleeding. CML is a triphasic disease characterized by an initial chronic phase that is relatively benign and can last for several years. If untreated, CML progresses to an accelerated phase and/or blast phase, which is associated with increasing symptoms and worsening hematologic parameters. This disease mainly affects adults during or after middle age with a median age of diagnosis at around 65 years. In USA, the annual incidence rate of CML is approximately 4800 cases.

The chief molecular marker involved in the etiology of CML is the BCR-ABL fused gene. The BCR-ABL gene is formed by the fusion of tyrosine kinase gene ABL1 with the BCR gene through reciprocal translocation between chromosomes 9 and 22 during formation of the Philadelphia (Ph) chromosome. The Ph-chromosome is identified in over 95% of patients with CML and represents the genetic hallmark of CML.describe the image Several in vitro studies showed that the tyrosine kinase chimeric protein Bcr-Abl encoded by the BCR-ABL gene is constitutively active in leukemia cells and has oncogenic properties. Bcr-Abl chimeric protein has been found to be associated with genomic instability and thereby suggested to be responsible for progression to advanced phases of CML.

The discovery of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, aimed at inhibiting the tyrosine kinase activation of Bcr-Abl by competitive binding at the ATP-binding site. Imatinib mesylate (Gleevec) was the first tyrosine kinase inhibitor (TKI), approved by the FDA in 2001 for the treatment of chronic phase CML. Patients treated with imatinib exhibited hematological and cytogenetic responses with no disease progression to the advanced phase. However, a significant proportion of patients with CML did not achieve a satisfactory long-term response to imatinib treatment due to acquired resistance which is often caused by the mutation of the BCR-ABL gene. Both in vitro and in vivo studies discovered more than 90 mutations which are suggested to be associated with imatinib-resistance.  Among these mutations the “gate-keeper” mutation T315I appears to be the most common and present in up to 20% patients with CML. This mutation originated as a result of substitution of a threonine (T) residue with isoleucine (I) at amino acid position 315. Crystallographic analysis revealed that BCR-ABL gene mutations cause conformational changes in the ABL-kinase domain that interfere with imatinib binding, resulting in 30 to 40% resistance to imatinib.These findings led to the development of more potent 2nd generation TKIs – dasatinib (Sprycel) or nilotinib (Tasigna™). During clinical studies major cytogenetic response was observed in 35 to 63% of patients treated with dasatinib or nilotinib. In 2010 both TKIs received FDA approval for the treatment of CML patients who are resistant or intolerant to imatinib. Even though dasatinib and nilotinib showed efficacy against a number of imatinib-resistant mutants in CML, they are ineffective against subsets of mutants. In addition, imatinib, dasatinib, and nilotinib failed to show efficacy against the T315I mutant. Therefore, since until recently, the T315I mutation remained a clinical challenge in patients with primary or secondary resistance to dasatinib or nilotinib, whether their disease is newly diagnosed or imatinib-resistant.

A study published in The New England Journal of Medicine (November 29, 2012) by Cortes et al., reported the success of overcoming BCR-ABL T315I mutation mediated resistance to TKIs in CML with a new small-molecule TKI ponatinib (AP24534). In in vitro studies, potent activity of ponatinib was observed against all mutant forms of BCR-ABL (including T315I) at a concentration as low as 40 nM. In the phase I dose-escalation study of ponatinib, Cortes et al. observed complete cytogenetic response and major molecular response in CML patients with non-T315I mutations.describe the image Among chronic-phase CML patients with T315I mutation 100% exhibited hematologic response, 92% had a major cytogenetic response, 75% exhibited complete cytogenetic response, and 67% had a major molecular response. The most common side effects reported in the study include hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. Clinically promising similar results were also observed in the PACE trial, a multicenter, international, single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy. On December 14, 2012, the FDA approved ponatinib (Iclusig tablets) for the treatment of adult patients with all phases of CML that are resistant or intolerant to prior tyrosine kinase inhibitor therapy.

 

References:  

1.         O’Hare T, Deininger MW, Eide CA, et al. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011;17:212-221.

2.         Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088.

3.         Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer. 2012;118:3123-3127.

4.         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;16:401-412.

5. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm332368.htm

About Arup Chakraborty

Arup Chakraborty is postdoctoral research fellow at the National Cancer Institute, Bethesda, MD. He earned a doctoral degree from Texas Tech University, and his primary research interest is in the field of clinical cancer mainly in mechanisms of resistance to molecularly targeted therapies