Understanding Oncogenic Tyrosine Kinase Fusion Driven Cancer: An Investigation into Inflammatory Myofibroblastic Tumor and the Non-kinase Fusion Partner
Childress, Merrida Ann
:
2018-11-16
Abstract
The study of oncogenic tyrosine kinase fusions began with the discovery of the t(9:22) translocation in chronic myelogenous leukemia and its chimeric protein product, BCR-ABL. Since then, chromosomal rearrangements resulting in activated tyrosine kinase fusions have been found in many other liquid and solid tumors. Inflammatory myofibroblastic tumor (IMT), a rare, mesenchymal neoplasm occurring primarily in the soft tissue and viscera of children, adolescents, and young adults, has been known to harbor ALK tyrosine kinase fusions in 50-60% of tumors, and ROS1, PDGFRB, RET, and NTRK3 fusions have also recently been detected in the ALK fusion negative cohort. Interestingly >30 5’ partner genes have been reported for ALK across all cancer types, and IMTs have displayed the greatest diversity in ALK fusion variants within one disease type. Currently, there is little data to address the question of how a different fusion partner may affect pretreatment clinical characteristics, disease responsiveness to targeted therapies, or acquired resistance. As next-generation sequencing technologies come to the forefront of clinical diagnostics, clinicians will know both the 5’ partner and the 3’ kinase involved in the fusion. Therefore, it is imperative that we determine the therapeutic implications of the kinase fusions differing by the 5’ partner protein. Additionally, beyond the presence or absence of a kinase fusion, nothing else is known about IMT on the genomic and transcriptomic level, leaving no rational therapies for fusion negative patients. The goal of these studies is to provide the specific pre-clinical data needed to more precisely direct clinical treatment as well as potential innovative treatment strategies for kinase fusion positive cancers such as IMT. Herein, I discuss the current knowledge surrounding IMT, the biology of ALK fusions, and the treatment of ALK fusion positive cancers. I also report on our study findings regarding the genomic and transcriptomic landscape of IMTs; how ALK fusion partners affect cellular phenotypes, biochemical properties of the fusion protein, and ultimately sensitivity to ALK tyrosine kinase inhibitors, and follow with a discussion of results and future directions.
Files in this item
This item appears in the following collection(s):
Related items
Showing items related by title, author, creator and subject.
-
Thaker, Tarjani Mahesh (2013-12-09)Department: BiochemistryThe G protein coupled receptor (GPCR) family is comprised of ubiquitous, membrane-bound proteins that are highly conserved in structure, yet varied in their cognate ligand. This allows for regulation of diverse physiological ...
-
Thiel, Kristina Wyatt (2007-10-03)Department: BiochemistryThe ErbB family of receptor tyrosine kinases regulates cell growth, differentiation, and tumorigenesis. This dissertation contains two independent studies of ErbB-1 and ErbB-4. In one study, the intracellular juxtamembrane ...
-
Fang, Wei Bin (2008-08-25)Department: Cancer BiologyThe EphA2 receptor belongs to the recently cloned Eph family of receptor tyrosine kinase (RTK). High levels of EphA2 RTK have been detected in 60-90% of human breast cancer specimens, both in breast cancer cells and in ...