High Grade Serous Carcinoma (HGSC) accounts for the majority of diagnosis and deaths for patients with Ovarian Cancer (OvCa). HGSC is commonly diagnosed in the advanced stage which is associated with poor prognosis. While patients initially respond quite well to first line therapeutic interventions the majority of initial responders will eventually relapse and develop chemoresistance disease. Second line therapeutic approaches display limited efficacy and the lack of novel druggable target discovery and lack of novel therapeutic strategies in HGSC have contributed to the poor prognosis associated with advanced stage HGSC. IRAK1 has been shown to represent a novel therapeutic target in several solid cancers and small molecule kinase inhibitors have displayed considerable efficacy in both in vitro and in vivo models. In this study we have shown that IRAK1 plays important roles in the growth of HGSC cells in vitro. IRAK1 knockdown was observed to result in reduced proliferation, colony formation, anchorage independent growth, migration / invasion and HER4 expression. Additionally, the small molecule kinase inhibitor pacritinib was observed to result in reduced colony formation, anchorage independent growth, 3D viability and growth factor receptor activation. SHP2 has previously been shown to represent a therapeutic target in GAB2 overexpressing OvCa where the allosteric inhibitor SHP099 displayed efficacy in vitro and in xenograft models of OvCa. We have shown that higher SHP2 mRNA expression is associated with reduced overall survival in serous OvCa and that SHP2 protein expression is significantly higher in high stage (3+4) HGSC compared to both stage 1 HGSC and normal adjacent tissue. Treatment with SHP099 was observed to display good efficacy in reducing 3D growth and viability of HGSC cells in vitro and impair nucleotide metabolism pathways through reducing RRM2 and TK1 expression. Finally, the combination of pacritinib and SHP099 resulted in a synergistic reduction in 3D growth and viability of HGSC cells in vitro. Following combination treatment, we observed synergistic reduction in 3D growth and viability of HGSC cells. Proteomics and Western blot analysis led to the observation that apoptotic cell death is elevated in pacritinib and SHP099 combination treated of OvCa cell lines. These findings indicate the combination of pacritinib and SHP099 may represent a novel therapeutic strategy in HGSC.