The Receptor Tyrosine Kinase ROR2 Is a Novel Marker for TSC-Associated Lesions and a Potential Therapeutic Target Independent of the TSC/mTOR Pathway
Robert T Sweeney, Edris Badreddin, Kelli D Montgomery, Roeland Nusse, Matt van de Rijn. Stanford University School of Medicine, Stanford, CA
Background: The expression of ROR2, a receptor tyrosine kinase, has been correlated with invasiveness of cancer cell lines as well as with poor clinical outcome for patients with gastrointestinal stromal tumor (GIST) and leiomyosarcoma (LMS). ROR2 is not expressed in the majority of adult normal tissues. Lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AML) are lesions that occur in the setting of tuberous sclerosis complex (TSC) and are characterized by disregulation of the mTOR signaling pathway. LAM and AML are treated clinically using mTOR inhibitors.
Design: We evaluated ROR2 protein expression by immunohistochemistry in LAM and AML samples and compared its diagnostic utility with current LAM and AML markers, HMB-45 and B-catenin; 12 cases of AML and 9 cases of LAM from patients with unknown TSC status and 15 cases of AML and 3 cases of LAM from TSC patients were studied. In vitro, we assayed drug responses to mTOR inhibitors in isogenic cell lines either over-expressing ROR2 or with reduced ROR2 expression. We also examined the transcriptional variation of TSC genes as a function of ROR2 over-expression or knockdown in these cell lines.
Results: By immunohistochemistry, ROR2 outperforms both HMB45 and B-catenin as a diagnostic marker for LAM with low background staining. Of the LAM cases, ROR2 stained nine strongly, two moderately strong, and one weakly. ROR2 staining was positive in 10/12 AML from patients of unknown TSC status and in 14/15 AML from patients with confirmed TSC mutations. In vitro studies on AML, GIST and LMS cell lines revealed that ROR2 expression did not mediate differential response to mTOR inhibitors, nor did it have a significant effect on the transcriptional control of TSC genes.
Conclusions: ROR2 is a novel diagnostic marker for LAM and AML and is a potential therapeutic target that is likely independent of the TSC/mTOR pathway.
Tuesday, March 20, 2012 2:15 PM
Platform Session: Section D, Tuesday Afternoon