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.