Congratulations to Dana Neel, who will be giving her thesis seminar titled, "ROS1 Fusion Partner Dictates Downstream Signaling Pathway Addiction in a Localization-Dependent Manner." If you can, please come out to support Dana as she finishes up her graduate work!
When: Thursday, December 14th, 4:00pm
Where: Genentech Hall, Room 114, Mission Bay
Dana is doing her graduate work in the Biomedical Sciences program as a member of Trever Bivona's lab.
Abstract: Lung cancer is the leading cause of cancer-related death in the United States. Receptor tyrosine kinase (RTK) fusions are recently described drivers in lung adenocarcinoma that arise from chromosomal rearrangements, resulting in the C-terminal kinase domain of an RTK attached to a variety of N-terminal fusion partners. ROS1 fusions involve several distinct N-terminal partners which lack any unifying protein domains or functions, and the significance of these individual partners on the biology of the fusions remained undefined. Here, we elucidate the importance of N-terminal partners in ROS1 fusions in mediating distinct subcellular localization of the fusions. This localization, in turn, dictates which downstream pathways these fusions are able to engage, which determines signaling pathway dependency in ROS1 fusion-positive cells. Specifically, we find that some ROS1 fusions are present on endosomes and are able to activate the RAS/MAPK pathway, while the most common fusion, CD74-ROS1, is found on the endoplasmic reticulum (ER), where it is unable to engage the MAPK pathway. Mislocalization of CD74-ROS1 off of the ER to the endosome results in activation of the MAPK pathway, demonstrating that localization is critical in driving downstream signaling pathway activation. Additionally, we find that cell lines expressing ROS1 fusions that are able to activate the MAPK pathway are dependent on this pathway for survival. We reveal that ROS1 fusions that can activate the MAPK pathway form more aggressive tumors and are less responsive to the targeted ROS1 inhibitor crizotinib in vivo. Currently, the presence of a ROS1 fusion in a tumor is identified using a breakapart FISH assay, which doesn’t identify the fusion partner. Our findings suggest that distinguishing the N-terminal partner in patients could be critical both for predicting tumor aggressiveness and response to targeted therapy, and for identifying what pathway a tumor depends on and thus may reactivate upon development of targeted inhibitor resistance. This could allow for stratification to specific upfront combination therapies to delay or prevent resistance from arising.