科研之友
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摘要
Defactinib (VS-6063, formerly PF-04554878) is a second-generation focal adhesion kinase 1 (FAK1) and proline-rich tyrosine kinase 2 (PYK2, FAK2) inhibitor. FAKs regulate cell signaling within the tumor microenvironment, including cell motility, survival and apoptosis and, as such, are an attractive target for drug development (1-3). Specifically in ovarian cancer, genetic and molecular data points to FAK as a target of key importance. The chromosomal region that encodes protein tyrosine kinase 2 (PTK2) (which in turn encodes FAK) is linked to increased susceptibility for ovarian cancer, and The Cancer Genome Atlas (TCGA) has reported increased FAK mRNA in high-grade serous cancers. These higher levels are correlated with poor survival (1, 4, 5). Defactinib has been shown to be a potent and selective reversible inhibitor of recombinant human FAK and PYK2 kinase. Preclinical data supported evaluation of this agent in clinical trials. Defactinib has been investigated in a phase I trial of patients with nonhematologic malignancies (NCT00787033). This trial demonstrated good pharmacokinetics with doses from 12.5 to 750 mg twice a day (b.i.d.) orally. Treatment was well tolerated and the recommended phase II dose was 425 mg orally b.i.d. Of note, stable disease was observed in several patients in this phase I trial with ovarian cancer, colorectal or biliary tumors, further supporting exploration in ovarian cancer (6). FAK has also been shown to increase sensitivity to chemotherapy across a number of preclinical tumor models. For example, FAK appears to increase sensitivity to gemcitabine in pancreatic models, and to 5-fluorouracil in colon cancer. How this increase in chemosensitivity occurred is not entirely known but may be related to FAK inhibitor-mediated reduction in nuclear factor-kappa B activity (3). In ovarian cancer, Kang et al. determined that inhibition of FAK with defactinib enhanced sensitivity of taxane-resistant cell lines to treatment with paclitaxel, a drug commonly used in ovarian cancer. This effect was related to FAK inhibition overcoming Y-box-binding protein 1 (YB-1)-mediated platinum resistance in an AKT-dependent pathway (7). This exciting work led to the phase I/Ib study of defactinib with weekly paclitaxel in recurrent ovarian cancer (NCT01778803). This trial has completed recruiting and was presented at ASCO 2014 (8). Inhibition of FAK holds promise as a therapeutic target across a number of tumor types and in combination with a number of cytotoxic and targeted therapies.
- 出版日期2014-11
