Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty-eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that makes the identification of a targetable biomarker in platinum and taxane resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxane-resistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease.

A Qualitative Transcriptional Signature for Predicting Recurrence Risk for High-Grade Serous Ovarian Cancer Patients Treated With Platinum-Taxane Adjuvant Chemotherapy

“…The DE genes were significantly enriched in 18 KEGG functional terms (hypergeometric test, FDR < 0.05, Figure 5C), including several functions related with platinum resistance for HGS-OvCa patients, such as PI3K-Akt signaling pathway (31), and cell adhesion molecules (32). In addition, some other functions have been reported to be related to taxane sensitivity for HGS-OvCa patients, such as focal adhesion (33), and cytokine-cytokine receptor interaction (34).…”

Lidocaine inhibits the metastatic potential of ovarian cancer by blocking NaV1.5‐mediated EMT and FAK/Paxillin signaling pathway

“…The FAK level was greatly increased in the late stage ovarian cancers, indicating the strong association of FAK with high metastasis and recurrence characteristics of ovarian cancer. FAK is also linked to the higher pathological stage, metastasis, and shorter overall survival rate, as well as drug resistance to platinum‐ and taxane‐based chemotherapy of ovarian cancer patients 27,28 . The recent successes in using small molecule FAK inhibitors in the clinical trials manifest the significance and function of FAK in ovarian cancer biology.…”

“…FAK is also linked to the higher pathological stage, metastasis, and shorter overall survival rate, as well as drug resistance to platinum-and taxane-based chemotherapy of ovarian cancer patients. 27,28 The recent successes in using small molecule FAK inhibitors in the clinical trials manifest the significance and function of FAK in ovarian cancer biology. 29 At clinically relevant concentrations, lidocaine was found to inhibit the angiogenesis of endothelial cells by inducing apoptosis and inactivating FAK/Paxillin signal pathway.…”

Strategies for Delivery of siRNAs to Ovarian Cancer Cells

“…Another target able to induce chemo-resistance is the Focal adhesion kinase (FAK) . This is a non-receptor tyrosine kinase of which the overexpression is present in 68% of epithelial OCs [94]. Moreover, FAK levels significantly correlate with shorter overall patient survival.…”

“…Moreover, FAK levels significantly correlate with shorter overall patient survival. Not only is FAK involved in the regulation of OC cell migration, invasion, adhesion, proliferation, and survival, it has recently been discovered that it promotes PTX resistance in OC as well as in other cancers [94]. Drug resistance is triggered via the promotion of MDR-1 activity.…”