Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment.

Derrick M Oaxaca,Georgialina Rodriguez,Jeremy A Ross,Joan G Staniswalis,Robert A Kirken,Sun Ah Yang-Reid

doi:10.1007/s13277-016-5179-7

Derrick M Oaxaca, Georgialina Rodriguez + Show 4 more

Open Access

https://doi.org/10.1007/s13277-016-5179-7

Copy DOI

Journal: Tumor Biology	Publication Date: Jul 21, 2016
Citations: 12	License type: CC BY 4.0

Affiliation: The University of Texas at El Paso

Abstract

Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.

Highlights

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, a chromosomal abnormality arising from a translocation between the long arms of chromosome 9 and chromosome 22 [1]
The imatinib-resistant BCR-ABL T315I mutation in CML has been associated with decreased overall survival rates when compared to non-mutation possessing patients [23]
Ponatinib has demonstrated potent efficacy in drugresistant forms of CML, including those harboring the T315I mutation; ponatinib has proven to be toxic at high concentrations [11, 24]

Summary

Introduction

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, a chromosomal abnormality arising from a translocation between the long arms of chromosome 9 and chromosome 22 [1]. CML is a neoplasm that originates from the hematopoietic lineage that is categorized by three distinct phases. The chronic phase (CP) is the most treatable and frequently diagnosed stage. The accelerated phase (AP) and blast phase (BP) are the least commonly diagnosed stages and represent end stage of the disease [2]. The Ph chromosome produces a constitutively active protein tyrosine kinase, BCR-ABL. Over the past 15 years, BCR-ABL has served as a hallmark for the identification of CML and has been extensively studied as a key target in the development of chemotherapies, such as imatinib

Methods

Results

Conclusion