Merrida Childress, Ph.D.
Postdoctoral Fellow, Savona Lab
Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although greater than 30 distinct 5’ fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 5’ partner is present. There are little data addressing how the 5’ partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKIs). We hypothesized that the 5’ partner influences the intrinsic properties of the fusion protein as well as the cellular functions that impact oncogenic potential and sensitivity to ALK TKIs. We generated clonal 3T3 cell lines stably expressing seven different ALK fusion variants. Using biochemical and cellular assays, we assessed efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. We calculated IC50s for 4 different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and noted 5-10 fold differences in drug sensitivity against the seven ALK fusions tested. Biochemical analyses revealed negative correlations between kinase activity and protein stability. Our results support the hypothesis that the 5’ fusion partner plays an important biological role that affects sensitivity to ALK TKIs. As kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies could have potential implications for other kinase-driven malignancies.
1. Jason L. Hornick, Lynette M. Sholl, Paola Dal Cin, Merrida A. Childress and Christine M. Lovly. (2015) Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors. Modern Pathology, 2015 May;28(5):732-9.
2. Douglas B. Johnson1, Merrida A. Childress, Zachary R. Chalmers, Siraj M. Ali, Samuel M. Rubinstein, David Fabrizio, Garrett M. Frampton, Jeffrey S. Ross, Sohail Balasubramanian, Vincent A. Miller, Philip J. Stephens, Jeffrey A. Sosman*, Christine M. Lovly* (2017) BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell and Melanoma Research, 2017 December;00:1-5.
MICTP T32 training grant 2014-2016 ( T32 CA009592)
F31 NRSA Grant ( F31 CA213744-02)