Disrupting the Scaffold to Improve Focal Adhesion Kinase–Targeted Cancer Therapeutics

Abstract

Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer.

Binding of the WASP/N-WASP-Interacting Protein WIP to Actin Regulates Focal Adhesion Assembly and Adhesion

“…These include Vasp, vinculin, zyxin, Myh9, Myl9, Tes, and Cyr61 (36,(52)(53)(54)(55)(56)(57)(58). In addition, FAK, the activation of which is regulated by WIP, plays an important role in tumor invasion and metastatic cell adhesion and has recently been a target for cancer therapy (59,60). It would be of interest to explore the potential role of WIP in cancer cell invasion and metastasis.…”

Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement

“…These kinases have an N-terminal four point ezrin/radixin/moesin (FERM) domain, a central tyrosine kinase domain, and a C-terminal focal adhesion targeting (FAT) domain [29]. The FERM domain facilitates the interaction of FAK and/or Pyk2 to growth-factor receptors, phospholipids, and additional proteins that are reviewed elsewhere [30, 31, 29]. The FAT domain binds to the intracellular domains of integrins to directly or indirectly recruit FAK or Pyk2 to focal adhesions [31, 29, 19].…”

Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15

“…The resistant Lovo-1 and thyroid K1 cells overexpressed ALDH1A3 and CD44 versus sensitive cells. Treatment with ALDH1A3 siRNAs or ALDH inhibitor, DEAB sensitized resistant Lovo-1 and K1 cells to Y15 inhibitor, biological cellular functions (Cance et al 2013). Recently, we found a novel autophosphorylation inhibitor, Y15, or inhibitor 14 that blocked cancer cell viability and inhibited tumor growth in breast (Golubovskaya et al 2008), neuroblastoma (Beierle et al 2010), pancreatic (Hochwald et al 2009), glioblastoma ) and colon cancer xenograft mice models Heffler et al (2013).…”