The objective of this proposal is to address a critical issue in cancer research - the molecular basis of drug resistance. The ultimate goal is to improve treatment response and overall prognosis in patients diagnosed with advanced cancer. We will use ovarian high-grade serous carcinoma (HGSC) as the disease model because it is one of the most aggressive cancer types in women. The development of resistance to chemotherapeutic reagents in HGSC represents a major challenge to achieving long term remission. To accomplish this goal, we have employed a proteomic method to compare global proteomes between primary and recurrent/post-chemotherapy HGSC tissues from the same patients. Among the preferentially expressed proteins identified in recurrent HGSCs, a non-receptor tyrosine kinase, Spleen Tyrosine Kinase (SYK), is of great interest. SYK is a non-receptor protein tyrosine kinase that is involved in signaling events that mediate diverse cellular responses, including proliferation, cell movement, differentiation, and phagocytosis. Small compound inhibitors such as Fostamatinib (AstraZeneca) and R112 (Rigel) are available and have been used in late phase clinical trials for patients with rheumatoid arthritis, auto-immune diseases, and hematopoietic malignancy. In our preliminary studies, we were able to show that total SYK and p-SYK (the active form) levels increased in recurrent post-chemotherapy tumors as compared to corresponding primary tumors from the same HGSC patients. We found that SYK inhibition cooperated synergistically with paclitaxel to inhibit tumor cell growth in vitro. A combination of SYK inhibitor and paclitaxel had the greatest anti-tumor effect in a mouse tumor xenograft model. We have applied quantitative proteomic analysis, SILAC (stable isotope labeling by/with amino acids in cell culture), to identify potential SYK substrates and discovered microtubule-associated proteins (MAPs) and tubulins that may contribute to aberrant microtubule dynamics in paclitaxel-resistant cancer cells. Based on our preliminary results, we hypothesize that SYK activation phosphorylates MAPs and tubulin, resulting in increased microtubule dynamics and thus antagonizing the effects of paclitaxel. SYK inhibitors could decrease the phosphorylation in MAPs or tubulin, rendering chemoresistant cells susceptible to paclitaxel treatment. Thus, targeting SYK signaling may reverse paclitaxel resistance and potentiate paclitaxel effects in HGSCs. The concept of targeting SYK in chemoresistant cancers is novel and highly translational. If our preclinical results turn out to be promising, SYK inhibitrs would warrant further evaluation in clinical trials.
The major objective of this study is to elucidate molecular mechanisms that lead to development of resistance to chemotherapeutic drugs in ovarian cancer, and to explore therapeutic strategies for reversing drug resistance. To this end, we have determined that the protein kinase, Spleen Tyrosine Kinase (SYK), is significantly more abundant in chemoresistant/recurrent ovarian tumors than in primary tumors from the same patients. This proposal is to demonstrate the important link between SYK and chemoresistance;the results are expected to lay a solid foundation for introducing new treatment regimen(s) to overcome drug resistance in ovarian cancer patients.
