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 harmone 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.

Keywords: ACK1; AKT; Drug resistance; Small molecule inhibitor; TNK2; Tyrosine kinase.