ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

Abstract

ACK1 tyrosine kinase, located on chromosome 3q29, is aberrantly activated, amplified or mutated in a wide variety of human cancers. While the deregulated kinase is oncogenic and its activation correlates with progression to metastatic stage, its inhibition causes cell cycle arrest, sensitizes cells to ionizing radiation and induces apoptosis. Oncogenicity of ACK1 is not only due to its ability to promote activation of critical pro-survival kinases and receptors by phosphorylating at distinct tyrosine residues, but also by employing a similar mechanism to eliminate a tumor suppressor from cancer cells. Despite the substantial data supporting the oncogenic role of ACK1, and the potential clinical benefit of blocking ACK1 in metastatic disease, to date ACK1-specific small molecule inhibitors have not been exploited for cancer therapy. This review highlights recent advances that elucidate how cancer cells employ ACK1 kinase to their advantage and discusses some of the novel ACK1 inhibitors that have shown promise in pre-clinical studies.

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

“…53,54 Furthermore, ACK1 has recently been implicated in cell spreading and migration, besides cell growth and survival, in multiple carcinomas. [55][56][57] It transduces extracellular signals to cytosolic and nuclear effectors via phosphorylated AKT1, as well as confers metastatic properties to drive cancer progression. 55 Hsp27, downstream to p38 MEK and implicated in dexamethasone and bortezomib resistance in MM cells, 45,46 can further promote migration and angiogenesis by NF-kB-dependent upregulation of VEGF gene transcription and secretion of VGFR2/ KDR in endothelial cells.…”

ACK1 Tyrosine Kinase Interacts with Histone Demethylase KDM3A to Regulate the Mammary Tumor Oncogene HOXA1

“…With multiple mechanisms promoting ACK1 activation in multiple cancers including breast cancer, ACK1 inhibitors have emerged as a potential therapeutic option for the treatment of hormone deprivation therapy-resistant tumors (16). Moreover, the availability of pTyr-1114 KDM3A antibodies will allow screening of breast cancer patients positive for ACK1 signaling and likely to acquire tamoxifen resistance.…”

“…Further, overexpression and activation are seen in multiple malignancies including breast cancer. Somatic autoactivating mutations and receptor tyrosine kinase (RTK) activation could also be utilized by cancer cells to achieve ACK1 overexpression (15)(16)(17)19). Overexpression of ACK1 in a human breast cancer cell line followed by injection into immunocompromised mice induced tumor development (20).…”

“…ACK1 is an ubiquitously expressed non-receptor tyrosine kinase that has been implicated in the processes of tumorigenesis, cancer cell survival, radiation resistance, and metastasis (15)(16)(17)(18)(19). ACK1 gene amplification is reported in several tumors including ovarian, cervical, and lung cancers (cBioPortal for Cancer Genomic, Memorial Sloan-Kettering Cancer Center) (20).…”

ACK1 promotes hepatocellular carcinoma progression via downregulating WWOX and activating AKT signaling

“…Such interactions result in ACK1-activated signal transduction through the activation of multiple downstream effectors including androgen receptor (AR) (17). Through these ACK1 activated signaling networks, ACK1 participates in cell survival, invasion, migration and tumorigenesis (18).…”