Gene rearrangements involving the anaplastic lymphoma kinase (ALK) represent a unique class of therapeutically targetable oncogenes that are increasingly being detected in numerous epithelial, mesenchymal, hematopoietic, and neural malignancies1. Importantly, ALK fusions have been identified in up to 8% of non-small cell lung cancer (NSCLC) and 50% of inflammatory myofibroblastic tumor (IMT)2,3. The prevalence of ALK fusions highlights the importance of understanding fusion kinase biology in order to develop the most effective therapeutic strategies. While the oncogenic fusion proteins resulting from ALK translocations are valid targets for cancer therapy, our understanding of how to most effectively target these fusions is lacking in comparison to other oncogenic drivers. For example, in EGFR-mutant NSCLC, different EGFR alterations confer varying degrees of sensitivity or resistance to EGFR directed therapies4-8. In addition, for other oncogenic fusions, such as the retinoic acid receptor alpha (RAR?) fusions found in subtypes of leukemia, it is known that the particular gene fused to RAR? not only affects response to therapy but also can be a therapeutic target itself8. Although many different 5' partner genes have been reported for ALK fusions, treatment of ALK fusion positive cancers is decided without regard to which 5' partner is present. For example, in NSCLC, patients with EML4-ALK, KIF5B-ALK, or TFG-ALK fusions are all treated with the ALK tyrosine kinase inhibitor (TKI), crizotinib. Clinically, ALK TKIs are effective for ALK fusion positive tumors; however, 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. Additionally, the role of each 5' partner has not been systematically investigated. Overall, we hypothesize that the 5' partner influences the intrinsic properties of the ALK fusion protein as well as the cellular functions that impact overall oncogenic potential, resulting in variability in disease phenotypes and response to targeted therapies. To test our hypothesis, we will carry out experiments using known ALK fusions detected in NSCLC and IMT to: 1) determine if the 5' partner alters kinase activity and efficacy of ALK TKIs, and 2) determine if the 5' partner of ALK fusions affects oncogenic cellular functions and explore mechanisms that may confer differential oncogenicity. Since more sophisticated next-generation sequencing technologies are coming to the forefront of clinical diagnostics, clinicians will not only know that a tyrosine kinase fusion is present, but also to which specific 5' partner the kinase is fused. Therefore, the findings from these studies are expected to refine the treatment of ALK fusion positive cancers in order to more effectively inhibit tumor growth and understand potential therapeutic resistance mechanisms. Furthermore, as kinase fusions are found in numerous malignancies, these studies may also have potential implications for other kinase-driven cancers.
Despite significant advances in treating ALK fusion positive cancers, the field currently has not refined the treatment of these cancers to accommodate for ALK fusion variant; therefor, additional studies are necessary to determine how the variant of the ALK fusion, defined by differences in the 5' ALK fusion partner, may dictate the therapeutic approach. This proposed research uses in vitro and in vivo models as well as patient tumor samples to understand the functional significance of the different ALK fusion variants. Findings from these studies are not only expected to provide rational for therapeutic decision-making of ALK fusion positive cancers but may also have potential implications for other kinase fusion-driven cancers, as kinase fusions are found in numerous hematologic and solid tumor malignancies.
|Johnson, Douglas B; Childress, Merrida A; Chalmers, Zachary R et al. (2017) BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell Melanoma Res :|