Abstract 5564: Dual inhibition of TTK and HSPA9 functions to synergistically decrease viability in triple-negative breast cancer cell lines

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype that is more likely to develop in African-American women and younger females. TNBCs have higher rates of metastasis, recurrence, and mortality and also lack effective targeted treatments. We have found that compared to normal tissue, expression levels of the mitotic kinase TTK are elevated in metastatic TNBC tumors, particularly in African-American patients. We have demonstrated in TNBC cell lines that inhibiting TTK reduces cell viability, proliferation, and survival. Unfortunately, none of TTK inhibitors currently available are suitable for clinical use. Therefore, in an effort to generate an accessible treatment, we targeted an interaction between TTK and the chaperone protein, HSPA9. This events leads to super-activation of TTK and we hypothesized that disrupting this event may serve as an alternative and more effective method for targeting TTK as a TNBC chemotherapeutic. Methods: We analyzed the effects of individual and combined inhibition of TTK and HSPA9 on cell viability in eight TNBC cell lines (i.e., BT-20, BT-549, CAL-51, HCC38, MDA-MB-231, MDA-MB-436, MDA-MB-453, and MDA-MB-468). AZ3146 and MKT-077 were used to inhibit TTK and HSPA9, respectively. The cells were first treated with each agent individually to determine the dose response profile and IC50 values. Then, to achieve therapeutically relevant dose combinations, cells were treated with IC20 doses of AZ3146 and sub-nanomolar (