The introduction of imatinib in 2001 made chronic myeloid leukemia (CML) a manageable disease for many patients. Tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are now routine therapy for patients with CML These inhibitors bind the kinase domain of BCR-ABL1, the fusion protein that is the molecular cause of CML. However, for some patients, BCR-ABL1 mutations lead to TKI-resistance and progressive disease. Our recent characterization of a new TKI, ponatinib, led to successful clinical trials to evaluate its efficacy for TKI-resistant CML. The key to ponatinib's success is is ability to kill cells with mutated BCR-ABL1. Unfortunately, for some patients, ponatinib therapy is only transiently effective due to onset of resistance. Analysis of pre- and post-ponatinib treatment samples suggests two mechanisms of ponatinib resistance: (1) two or more mutations per BCR-ABL1 molecule that prevent ponatinib binding and (2) survival despite non-mutated, inhibited BCR-ABL1 due to activation of alternative pro-survival/anti-programmed cell death pathways.
Aim 1 : Determine the role of BCR-ABL1 compound mutations in resistance to ponatinib and identify strategies to restore BCR-ABL1 inhibition. This information will enable clinicians to make confident treatment decisions starting at diagnosis. Sequencing the kinase domain before and during ponatinib treatment with the most advanced technology will allow for a more complete understanding of the complex leukemia population and provide further information about the role of mutations in TKI resistance.
Aim 2 : Identify alternative oncogenic pathways in primary CML specimens exhibiting resistance to ponatinib despite sustained inhibition of BCR-ABL1. TKI resistance is documented in patients whose BCR- ABL1 is not mutated, indicating anomalous activation of an endogenous survival pathway. To uncover these pathways and explore their suitability as therapeutic targets, we will screen patient samples using kinase inhibitor and siRNA libraries in conjunction with ponatinib. This will provide information about the mechanism of survival of each individual patient's leukemia and will begin building a road toward personalized therapy for TKI-resistant CML.
Aim 3 : Target STAT3 in TKI-resistant CML. Preliminary studies with TKI-resistant cell lines indicate STAT3 as a downstream integrator of aberrant signaling pathways in the setting of TKI resistance. We are working with a team of chemists to develop increasingly specific and active STAT3 inhibitors. We have innovated a rapid and robust luciferase screen that has already delivered the best known STAT3 inhibitors to the forefront of CML research. In summary, BCR-ABL1 compound mutations and alternative pathway activation are the sources of unmet clinical challenges in CML treatment and we propose a platform to design and implement new strategies to overcome both resistance mechanisms. Data from these studies will be critical for treating TKI-resistant CML patients and will impact therapy for many other drug resistant cancers.
Chronic myeloid leukemia (CML) was abruptly converted in 2001 from a fatal blood cancer to a manageable disorder by the introduction of 'magic bullet' drugs that target BCR-ABL1 kinase, the molecular cause of CML. However, some patients with CML encounter treatment failure due to: (1) BCR-ABL1 mutations that prevent drug binding or (2) resistance despite inhibition of BCR-ABL1, caused by activation of alternative signaling pathways. The proposed studies focus on developing strategies to predict and overcome drug resistance in treatment refractory CML. These findings will improve the use of targeted therapies in CML and many other cancers.
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