Abstract Many anti-tubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types of cancer, including ovarian, lung, and breast cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity. Protein tyrosine kinases (PTKs) play significant roles in cancer development, and many PTK inhibitors have been widely used for treatment of malignancies and in clinical trials. We conducted Phos-tag-based biochemical screenings to determine the regulation and function of PTKs during Taxol chemotherapeutics. In response to Taxol treatment, one of the most significant changes in the PTK family is the marked protein degradation of fibroblast growth factor receptor 4 (FGFR4). In addition, FGFR4 controls Taxol chemosensitivity in ovarian cancer cells. Importantly, FGFR4 expression levels are elevated in recurrent post-chemotherapy ovarian cancer patients. These preliminary results provide a strong premise in support of our hypothesis that the FGFR4 signaling functions as a therapeutic target for paclitaxel-based chemotherapeutics in treatment of drug-resistant and/or recurrent patients. We will test our central hypothesis by two specific aims. Aim 1: Determine how FGFR4 is regulated during Taxol treatment; Aim 2: Targeting FGFR4 to overcome paclitaxel chemoresistance in ovarian cancer. The identification of new regulators and/or signaling pathways triggered by anti-tubulin drugs will shed light on the mechanisms underlying chemoresistance. Our study identifies the FGFR4 signaling as a potential therapeutic target in recurrent ovarian cancer and suggests that combining selective inhibitors of FGFR4 (in clinical development) with Taxol will have enhanced efficacy in the treatment of chemo-resistant and/or recurrent patients.