Schoolmeester, Kenneth

Abstract Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.

INTRODUCTION: Leiomyomas are benign uterine smooth muscle tumors. After menopause, most women have a reduction in size and number of leiomyomas. Conversely, uterine sarcomas present as a rapidly enlarging pelvic mass in postmenopausal women. The distinction of uterine leiomyoma from sarcoma is difficult and definitive diagnosis requires pathologic examination. METHODS: A 74 year-old multiparous female with a history of ductal carcinoma in situ (DCIS) of the breast presented with significant postmenopausal bleeding, requiring blood transfusion, and a rapidly enlarging pelvic mass. Abdominal imaging including ultrasound and computerized tomography confirmed a 15 cm uterine mass. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy with concern for uterine sarcoma. Grossly, the uterus contained a 15.5 cm well demarcated intramural mass. Microscopically, the tumor was a spindle cell neoplasm with anastomosing fascicles interrupted by thick-walled blood vessels or fibrous regions. The cells exhibited uniformly mild to moderate cytologic atypia. Immunohistochemically, the tumor strongly and diffusely expressed desmin and h-caldesmon and exhibited patchy, strong expression of CD10. RNA-seq, confirmed by RT-PCR and Sanger sequencing, revealed a gene fusion involving KAT6B and KANSL1. The fusion joins exon 3 of KAT6B to exons 11 and 12 of KANSL1. The final diagnosis was a benign uterine leiomyoma. The patient remains without evidence of disease six months post-operatively. CONCLUSION: This is the first case, to our knowledge, that has identified the KAT6B-KANSL1 fusion in a uterine leiomyoma. Further efforts to classify the pathologic characteristics and prevalence of this fusion may contribute to understanding of tumorigenesis of uterine smooth muscle tumors.