TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple-Negative Breast Cancer

Triple-negative breast cancers or TNBCs do not express estrogen receptor (ER), progesterone receptor (PR), and Her2/neu receptor tyrosine kinase (HER-2) proteins. TNBCs are highly aggressive cancers with poor prognoses and have high risks of relapse. Unlike other ER/PR/HER2-positive type of breast cancer, for which excellent therapeutic measures are available, TNBC patients do not respond to most currently available targeted therapeutic agents. Hence, identification of new therapeutic targets and inhibitors that suppress TNBC tumor growth is an urgent need within the clinical and research communities. We have used advanced mass spectrometry-based proteomic and molecular biology approaches to systematically analyze a panel of TNBC-derived cell lines. This comprehensive study across 25 different TNBC-derived cell lines has allowed us to identify a protein tyrosine kinase, TNK2 (also known as ACK1), that plays a crucial role in TNBC growth and invasion. Further, we discovered that inhibiting TNK2 expression using small RNA interference dramatically suppressed TNBC tumor growth in preclinical tumor transplantation animal models. Most importantly, we identified a potent TNK2-specific small-molecule pharmacological inhibitor, DZ1-067, which not only suppressed TNK2 activation, but also significantly suppressed TNBC cell growth, suggesting that we have identified both a drug target for TNBC treatment and an effective drug compound. Based on data generated during preliminary studies, we hypothesize that TNBC tumor growth may be dependent on the activation of TNK2 protein and that inhibition of TNK2 will be beneficial to women with TNK2-positive TNBCs. To test this hypothesis, for this proposal, we will extend our research efforts, first by classifying a much larger (>800) collection of breast tumor specimens to determine if TNK2 activation is a dominant feature shared across all analyzed patient specimens. Secondly, TNK2-specific small molecule inhibitor, DZ1-067, will be utilized to monitor suppression of TNBC xenograft tumor growth and their metastasis in immunocompromised mouse models. Lastly, in parallel to the two experiments above, we will also perform global phosphoproteomic analysis of dissect the tumorigenic signaling pathways driven by TNK2-dependent phosphorylation. The success of the proposed project will be evident in (i) identification of the protein kinase TNK2 as a novel therapeutic target for TNBCs and (ii) inhibition of TNK2 with DZ1-067 as a clinically effective strategy for TNBC treatment. New Food and Drug Administration stage I and stage II clinical trials based on the TNK2 pharmacological inhibitor could stem from our proposal to evaluate the efficacy of inhibiting TNK2 in TNBC patients. This proposal thus has the very real potential to provide an effective therapeutic strategy to reduce the recurrence and metastasis and improve the prognosis of patients with TNBCs.